The objective of this study was to compare the safety and efficacy of mirtazapine and escitalopram in HIV patients for the treatment of depression. Methods: In this trial, 70 adult HIV patients with major depression were randomized and assigned to receive 8 weeks of daily open label mirtazapine (5-30mg) or escitalopram (7.5-20 mg). The primary outcome variables were endpoint response in Hamilton Rating Scale for Depression (HAM-D) score and change of HAM-D score from baseline to endpoint. Patients having improvement of > 50% on the HAM-D total scores during treatment were considered to have responded. A final 17-item HAM-D total score of 8 or less defined remission. Results: The response rate was 91.4 % (32/35) in Mirtazapine group and 85.7 % (30/35) in Escitalopram group (p= 0.71). The remission rate was more in escitalopram group (48.6 %, 17/35) compared to Mirtazapine group (34.3 %, 12/35); however it was not statistically significant (Chi square (1, N = 70) = 2.1, p = 0.22). After controlling for baseline score, the median HAMD score at 8 weeks was significantly lower in the Mirtazapine group (Median (Mdn)=4, Interquartile range (IQR)= 11) compared to Escitalopram group (Mdn=13, IQR= 12) (p < 0.001). The number of adverse events reported was more in Escitalopram group (110) than Mirtazapine group (85); however this was not statistically significant (p= 0.34). Conclusions: Both these drugs are useful in the management of depression in HIV patients and need further study.