Mental health problems are the leading cause of disability in Canadian workers. Medication ineffectiveness is hypothesized to increase the time to return-to-work in these workers. We assessed whether prescription changes based on pharmacogenomics profiling (RxReport®) improved medication effectiveness in patients on mental health-related disability. In this retrospective cohort analyses, we assessed the impact of pharmacogenomic profiling on patient outcomes in 84 Canadian workers who were on a mental health-related disability between May 2018 and May 2019. All patients completed an informed consent form and a standard questionnaire including medical history, medications, disease symptoms, and medication side effects. Licensed pharmacists made recommendations for prescription changes in 83 patients. The main study outcome was medication effectiveness defined on a scale of 0 to 10 (0 being most effective and 10 being most ineffective) based on reported mood toward regular work tasks and medication side effects. We compared the medication effectiveness at baseline and at 3 months after the pharmacogenomics-based prescription changes. This retrospective cohort analyses included 46 patients who completed the follow-up questionnaires. Of them, 54% (n = 25) were females, 67% (n = 31) were Caucasians, and the mean age was 38 years (standard deviation [SD] = 11). The average baseline effectiveness score was 8.39 (SD =1.22). Following the prescription changes, the medication effectiveness scores significantly improved to an average of 2.30 (SD = 1.01) at 3 months of follow-up (effect size r = 0.62, p = <0.001). Pharmacogenomics could help in improving treatment outcomes in patients on mental health-related disability.