Background: The predominant contributor to psychiatric disability across the globe is depression. Hence; the present study was conducted for comparing the efficacy of Crocus sativus L. with fluoxetine for improving depression among patients with cardiovascular diseases. Materials & methods: A cohort of 40 patients aged between 20 and 60 years was recruited for the study. Inclusion criteria mandated that participants had a diagnosis of any form of cardiovascular disease and fulfilled the DSM IV-TR criteria for depression. The Hamilton Depression Rating Scale (HDRS), established by Hamilton in 1960, was employed to evaluate the severity of depressive symptoms.The patients were randomly assigned. All the results were recorded in Microsoft excel sheet and were subjected to statistical analysis using SPSS software. Results: Mean age of the patients of saffron group and fluoxetine group was 41.9 years and 44.7 years respectively. Baseline to 6 weeks change of HDRS score among patients of the saffron group and fluoxetine group was 11.7 and 12.1 respectively. Among saffron group, dry mouth and constipation was seen in 5 percent of the patients each. Among the Fluoxetine group, drowsiness, dry mouth and constipation was seen in 5 percent, 10 percent, and 20 percent of the patients respectively. Conclusion: Both the drugs showed similar efficacy in terms of improvement and incidence of adverse events in managing depression among patients with cardiovascular diseases.