Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine and sertraline, are widely prescribed for depression due to their favorable safety profiles compared to older antidepressants. However, these medications are associated with various adverse drug reactions (ADRs) that may affect patient adherence and treatment outcomes. This study evaluated the prevalence and characteristics of ADRs in outpatients treated with fluoxetine and sertraline, comparing ADR rates in real-world clinical settings. A prospective cross-sectional study was conducted at a tertiary care psychiatric hospital from July to December 2018, involving 65 outpatients with depression who had been on fluoxetine (N=47) or sertraline (N=18) for at least four weeks. Data on ADRs were collected using a validated questionnaire, and comparisons were performed using Chi-square and Fisher’s Exact tests. The mean age of participants was 47.55 ± 16.14 years for fluoxetine and 45.16 ± 19.47 years for sertraline, with no significant differences in gender or treatment duration. Common ADRs included sedation, insomnia, and gastrointestinal symptoms. Anorexia was significantly more frequent in the fluoxetine group (21.28%, P=0.05), while nausea/vomiting was higher in the sertraline group (27.78%, P=0.001). Other ADRs, including sexual dysfunction and cardiovascular effects, were similar between groups. These findings underscore the importance of recognizing distinct ADR profiles to optimize treatment decisions for outpatients with depression.