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Abstract Background Inappropriate medication use among individuals with depressive disorders (DD) is a rising public health challenge. We aimed to investigate the polypharmacy and its determinants among individuals with DD in a less developed region, and evaluate the pattern of medication use in this population. Methods Data was extracted from Pars Cohort Study (PCS) between 2016 and 2019. Participants were asked to bring all the medication they were using regularly, and history of DD during the last 12 months prior to study was obtained. The Anatomical Therapeutic Chemical classification was applied and polypharmacy was defined as concurrent use of five or more medications. Logistic regression models were developed to estimate the associations between polypharmacy and DD, adjusted for relevant covariates. The prevalence of consumption of each drug class was estimated among males, females, and elders. Logistic regression was applied and the adjusted odds ratio (OR) and its 95% confidence interval (CI) were estimated. Results A total of 9264 participants with a mean age of 52.6 (SD: 9.7) were enrolled. The prevalence of polypharmacy was 22.6% [95% CI (20.7–24.6)]. The most common drug classes were genitourinary system (55.4%) and nervous system (29.1%) medication, respectively. Recent history of DD was reported among 19.4% (n = 1795) participants, the majority of whom were females. Factors associated with polypharmacy include female gender (OR: 1.51), Fars ethnicity (OR: 1.52), lower physical activity (OR: 1.74), and higher socioeconomic status (OR: 1.40). The prevalence of antidepressant use among males was higher than females (P