This study aimed to compare drug adherence behaviors during the sixth week between patients with first diagnosed major depressive disorder who received the Drug Adherence Enhancement Program and those who received only the usual care. A randomized clinical trial, post-test only design was conducted in the outpatient-unit of a medical school hospital in Bangkok, Thailand. The experimental and control groups consisted of 30 and 26 participants respectively. Participants in the experimental group exhibited significantly higher drug adherence behaviors than the control group. This is important for nurses in promoting adherence to antidepressant drugs for patients with first diagnosed major depressive disorder.