Objectives: Clostridioides difficile infections represent a growing global problem, and accordingly there is a need to find new potential patients with an increased risk of infection. Considering the widespread use of psychotropic drugs and their various mechanisms of action and effects in the gastrointestinal system, the aim of the study is to examine the connection between the use of psychotropic drugs and the occurrence of recurrent Clostridioides difficile infections. Patients and Methods: A retrospective cohort study was conducted, which included subjects over the age of 60, who were hospitalized at the Clinic for Infectious Diseases "Dr. Fran Mihaljević" in Zagreb in the period from 2016 to 2019 for the first episode of CDI. The patient cohort consists of patients in two groups: those who were not rehospitalized for rCDI within three months of discharge and those who were hospitalized for rCDI within three months of the first episode. The necessary clinical, laboratory and microbiological data on the patients were collected from the patient records, and psychotropic drugs were divided into six groups for the purpose of this research. Results: A total of 305 subjects were included in the study, of which 180, i.e., 59% were women, with an average age of 78 years (IQR (interquartile range) 71-83 years). Within the entire cohort, 106 (34.8%) patients developed recurrent CDI within 90 days of hospitalization or completion of therapy for the first episode (a total of 171 CDI episodes). Of these patients, 76 developed rCDI by day 28, and 99 by day 90. Psychopharmaceuticals are used in chronic therapy by a significant number of patients out of the total number of respondents (59.8% vs. 62.3%), equally in one and the other group. No difference was found in the use of psychotropic drugs between patients who developed rCDI compared to those who had only one episode of CDI. Conclusion: This research did not find a statistically significant association between the use of psychotropic drugs and recurrent C. difficile infections, however, psychotropic drugs are a very complex drug group whose use is extremely wide, and new knowledge about the influence of the microbiome on the central nervous system and vice versa points to the importance of new research.