Background: Chronic neuropathic nonodontogenic orofacial pain (OFP) is the leading symptom of a wide range of diseases, which can exist independently, without other clinical signs or symptoms and without abormalities in radiological or laboratory findings. OFP is a disease which should be treated adequately. Its successful treatment depends on the early diagnostics and understanding of the mechanisms of its occurrence. The most frequent clinical entity in our sample was nonodontogenic trigeminal neuralgia, the fifth cranial nerve disorder characterized by bouts of intense, sharp pain which usually affects one or two branches of the nerve on one side of the face. In most cases, the exact cause of trigeminal neuralgia has not been completely clarified. OFP causes emotional, psychological and social disorders, which can significantly affect the quality of life of the affected person. Aim of study: The aim of the research is to compare the estimated health-related quality of life and the degree of depression of patients with OFP with healthy control subjects, using a validated Croatian version of the SF-36 Health Survey Questionnaire and the Beck Depression Inventory II. Patients and Methods: The controlled cross-sectional study included 100 patients aged between 18 and 75, with the clinical diagnosis of OFP in duration of at least six months (72 females and 28 males), and 119 healthy subjects (73 females and 46 males) as a control group. A standardized diagnostic protocol was applied to both the patients and the control group: 1) demographic data and quantitative estimate of pain on the visual analog scale (VAS); 2) evaluation of presence of neuropathic pain measured by the Leeds Assessment of Neuropathic Signs and Symptoms (LANSS); 3) evaluation of emotional status using the Beck Depression Inventory II, and 4) assessment of health-related quality of life using the SF-36 Questionnaire. The Kolmogorov–Smirnov Test analyzed the normality of data distribution, and, in keeping with the results, suitable nonparametric tests were used in further data processing. Quantitative data were shown through medians and interquartile range, while the nominal and categorical data were presented through absolute frequencies and the corresponding relative frequencies. The difference in the continued values between the groups were analyzed using Mann-Whitney U Test, while the differences between the nominal and categorical values were analyzed using Chi-Square Test. Spearman's rank correlation coefficient between individual clinical parameters was calculated. All P values smaller than 0.05 were considered statistically significant. Results: The average LANSS score for the patients was 17.18, and for the control group 0. The average BDI-II score for the patients was 18.31, as opposed to 5.87 for the control group. The Mann-Whitney U Test for each of the nine categories that measure SF-36, shows statistically significant difference between the affected and healthy subjects. In all the categories except one (Vitality), the control group has a higher index than the group with OFP. The result of the control group was equal or greater than 60% of the possible overall result in seven out of nine categories, while the treatment group did not exceed the limit of 60% in any of the categories. A statistically significant correlation was noted between the degree of depression and the SF-36 domains of Physical Functioning (PF), Body Pain (BP), General Health Perception (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE) and Mental Health (MH). No statistically significant correlation was proven between the degree of depression and the domains of Role Physical (RP) and Health Transition (HT). Conclusion: Chronic neuropathic nonodontogenic orofacial pain causes depression and affects almost all the determinants of quality of life measured by SF-36 Questionnaire. There is a strong correlation between depression and low quality of life in patients with OFP.