Background Depression is a common psychiatric disorder worldwide, including in Iran, and is estimated to affect 10%–15% of the population. Antidepressant drugs can have multiple side effects, so a good choice of drug is important for successful treatment. This study compared the efficacy of nortriptyline with that of fluoxetine in the treatment of patients with major depressive disorder and assessed related factors, including age, gender, and level of education. Methods The study was a double-blind, randomized clinical trial with a six-month follow-up period. Participants were 120 patients aged 15–60 years with a diagnosis of major depressive disorder based on a psychiatry interview and the Beck depression rating scale, which were performed at the beginning, middle, and end of the study. The patients were treated with nortriptyline or fluoxetine. The paired t-test, independent t-test, and the k chi-square test were used to analyze the data. Results Twenty-three patients dropped out and 97 remained in the trial. Before intervention, the mean depression score was 32.85 ± 6.23 in the nortriptyline group and 33.12 ± 6.50 in the fluoxetine group. The results of the independent t-test showed a significant difference between depression score means before and after treatment in both groups. Changes at the end of the trial compared with baseline scores were 13.4 ± 4.68 and 16.96 ± 4.96 for nortriptyline and fluoxetine, respectively. Paired t-testing showed a significant difference in the mean depression score for both the nortriptyline and fluoxetine groups. Age, gender, and level of education had no significant effects on the outcome of treatment in the two groups. Conclusion The present study suggests that both nortriptyline and fluoxetine were effective in the treatment of depression, but that fluoxetine was more effective than nortriptyline after 3 and 6 months of treatment.