Objectives: Oral lichen planus (OLP) and primary burning mouth syndrome (BMS) are two oral psychoneuroimmunoendocrinological diseases. The objectives of our study were to determine the concentration/activity of stress (cortisol, α-amylase) and inflammatory (IL-6) salivary biomarkers, psychological profile, and quality of life (QoL) in patients with OLP and patients with primary BMS. We observed the influence of disease duration and symptom intensity (pain/burning) on the concentration/activity of salivary biomarkers. The hypothesis of this study was that higher concentration of salivary cortisol and IL -6 and higher salivary-αamylase activity in patients with OLP and primary BMS correlate with poorer mental health (higher levels of depression, anxiety, stress) and lower QoL. Subjects and Methods: A total of 160 subjects, divided into three groups, participated in this case-control study: 60 patients with a clinically and histopathologically confirmed diagnosis of OLP; 60 patients diagnosed with primary BMS; and 40 control subjects. The group of patients with OLP was composed of 40 patients with an erosive form of the disease and 20 patients with a non-erosive form. The control group consisted of randomly selected patients who came to the Department of Diagnostic Radiology, Dental Clinic Split, Split, Croatia. Medical history data, a list of medications, and disease duration (months) were obtained from all subjects. Unistimulated whole saliva (UWS) was collected between 9 and 10 am to avoid diurnal variation. Approximately 2.00 to 2.50 mL of saliva was collected from all subjects in graduated tubes (Salivette) using the „spit method.“ Salivary cortisol and IL-6 concentrations were analyzed by the immunochemical method of enzyme-linked immunosorbent assays (ELISAs). Salivary α-amylase activity was measured by the kinetic colorimetric method. The Visual Analogue Scale (VAS; ranging from 0 to 100 mm) was used to assess the intensity of pain and/or burning in patients with OLP and BMS. The psychological evaluation of each subject was assessed with the Depression, Anxiety, and Stress Scale (DASS-21, Lovibond & Lovibond, 1995a; Croatian adaptation Jokić-Begić, Jakšić, Ivezić and Surányi, 2012). QoL was assessed using the Croatian version of the Oral Health Impact Profile questionnaire (OHIP-CRO14). Results: The concentration/activity of salivary cortisol (0.44 vs. 0.52 vs. 0.44 µg/dl; p=0.306), α-amylase (145804 vs. 160531 vs. 179107 U/L; p=0.535) and IL- 6 (4.35 vs. 3.42 vs. 3.81 pg/ml; p=0.244) showed no statistically significant difference between patients with OLP, patients with primary SPU and control subjects. The patients with primary BMS had statistically significant higher VAS scores compared to patients with OLP (7.0 vs. 3.5) (p < 0.001). The patients with primary BMS had statistically significant worse psychological profile (higher scores for depression, anxiety, stress) (p < 0.001) and QoL (total) (p < 0.001) compared to patients with OLP and control subjects (Kruskal-Wallis test). Multiple linear regression showed a statistically significant effect of VAS on the level of depression, anxiety, and stress in patients with primary BMS (p < 0.001). There was a moderate positive correlation between symptom intensity (pain/burning) and psychological profile (depression, anxiety, stress) in patients with primary BMS (r = 0.373, p = 0.003; r = 0.515, p < 0.001; r = 0.365 , p = 0.004). There was a strong positive correlation between anxiety and depression (r = 0.643), stress and depression (r = 0.720), and stress and anxiety (r = 0.696) in patients with OLP (p < 0.001). There was a strong positive correlation between anxiety and depression (r = 0.652), stress and depression (r = 0.793), and stress and anxiety (r = 0.705) in patients with primary BMS (p < 0.001). Conclusion: This case-control study is the first to compare the psychoimmunoendocrinological profile of patients with OLP and BMS (two oral diseases with different etiopathogenetic mechanisms). The patients with primary BMS had higher concentrations/activities of salivary stress biomarkers (cortisol, α-amylase) and stronger association with psychological difficulties compared to patients with OLP and their possible causal role. Increased salivary concentrations IL-6 indicate a dominant inflammatory etiopathogenetic mechanism in patients with OLP. There was a strong positive correlation between anxiety and depression, stress and depression, and stress and anxiety in patients with OLP and BMS. This suggests the importance of cortisol and salivary α-amylase as stress biomarkers, considering the demonstrated strong association between BMS and mental disorders. An interdisciplinary psychoneuroimmunological approach is necessary for chronic diseases such as OLP and BMS because they are related to the patient's psychological state, regardless of whether mental disorders are a cause or a consequence.