Background The World Health Organization recommends that treatment of depression in low and middle-income countries with a scarcity of psychiatrists could be done in primary care and should include prescription of antidepressant medications for moderate and severe depression. Little is known, however, about the actual practices of antidepressant prescription by primary care physicians in low and middle-income countries, nor about adherence by people receiving such prescriptions. In a large study of primary care clinics in Goa, India, we examined the relationship of actual to recommended prescribing practices for depression, among all patients who screened positive for common mental disorder. We also examined other patient and clinic characteristics associated with antidepressant prescription, and self-reported adherence over a one-month period. Methods Patients attending 24 primary care clinics were screened for common mental disorders. Those who screened positive were eligible to enroll in a trial to assess the effectiveness of a collaborative stepped care (CSC) intervention for mental disorders. Physicians in the 12 intervention and 12 control clinics (usual care) were free to prescribe antidepressants and follow-up interviews were conducted at 2, 6 and 12 months. Screening results were shared with the physician, but they were blinded to the diagnosis generated later using a standardized diagnostic interview administered by a health counsellor. We categorized these later diagnoses as "moderate/severe depression", "mild depression or non-depression diagnosis", and "no diagnosis". We used a two-level hierarchical logistic regression model to examine diagnostic and other factors associated with antidepressant prescription and one-month adherence. Results Overall, about 47% of screened positive patients (n = 1320) received an antidepressant prescription: 60% of those with moderate/severe depression, 48% of those with mild depression or non-depression diagnosis, and 31% with no diagnosis. Women (OR 1.29; 95%CI 1.04-1.60) and older adults (OR 1.80; 95%CI 1.32-2.47) were more likely to receive an antidepressant prescription. While the overall rate of antidepressant prescription was similar in clinics with and without CSC, patients without any diagnosis were more likely to receive a prescription (OR 2.20 95% CI 1.03-4.70) in the usual care clinics. About 47% of patients adhered to antidepressant treatment for one month or more and adherence was significantly better among older adults (OR 3.92; 95% CI 1.70-8.93) and those who received antidepressant as part of the CSC treatment model (OR 6.10 95% CI 3.67-10.14) compared with those attending the usual care clinic. Conclusion Antidepressants were widely prescribed following screening in primary care, but prescription patterns were in poor accord with WHO recommendations. The data suggest under-prescription for people with moderate/severe depression; over-prescription for people with mild depression or non-depression diagnoses; and over-prescription for people with no disorders. For all diagnoses adherence was low, especially in usual care clinics. To address these concerns, there is an urgent need to study and develop strategies in primary care practices to limit unnecessary antidepressant prescriptions, target prescription for those patients who clearly benefit, and to improve adherence to antidepressant treatment. ClinicalTrials.gov Identifier: NCT00446407.