OBJECTIVES: The objective of this study was to examine factors associated with low adherence in Major Depressive Disorder (MDD) patients initiating antidepressant medication (ADM) over a 12-week period. METHODS: MDD patients initiating an ADM (with no ADM claim in the 6 months prior) were identified from a large pharmacy benefits manager database. Patients completed paper or online assessments including demographics at baseline and patient-reported assessments at baseline, Week 4 and Week 12. Participants were classified as having low, medium, or high adherence based on the modified Morisky Adherence Scale, with the medium and high adherence groups combined for analysis. Logistic regression analyses were run to evaluate the association between adherence and age, gender, and patient-reported assessments of depression and sexual dysfunction (SD), weight gain, sleep problems, nausea, and anxiety. RESULTS: Of 2,412 patients screened, 591 enrolled and completed baseline assessments. Mean age was 40.4 years (standard deviation=12.1), 82.4% were women, and 87.6% were white. There were 483 who completed Week 4 and 425 who completed Week 12 assessments. At Week 12, 39.6% were high adherers, 20.6% were medium adherers, and 39.8% were low adherers. Thirty-eight percent of low adherers had actually discontinued ADM. Among discontinuers, 40.6% discontinued due to ADM side effects. In logistic regression models, low adherence at Week 4 was significantly associated with weight change ≥5 pounds (OR=2.10, 95% CI: 1.32–3.35), anxiety (OR=1.73, 95% CI: 1.06-2.8) and nausea (OR=2.31, 95% CI: 1.06–5.02). Age, gender, depression severity, sexual dysfunction, and insomnia were not significant in the logistic model. No factors were significantly associated with adherence at Week 12. CONCLUSIONS: In this real-world study of patients with MDD, nearly 40% of patients were low adherers. Weight change, anxiety, and nausea were associated with low adherence at Week 4, but not at Week 12.