We performed a randomized trial to prevent depression relapse in primary care by evaluating intervention effects on medication attitudes and self-management of depression. Three hundred and eighty six primary care patients at high risk for recurrent depression were randomized to receive a 12-month intervention. Interviews at baseline, 3, 6, 9, and 12-months assessed attitudes about medication, confidence in managing side effects, and depression self-management. This depression relapse prevention program significantly increased: 1) favorable attitudes toward antidepressant medication [Beta = .26, 95% C.I. = (.18, .33)]; 2) self-confidence in managing medication side effects [Beta = .53, 95% C.I. = (.15, .91)]; 3) depressive symptom monitoring [O.R. = 4.08, 95% C.I. = (2.80, 5.94)]; 4) checking for early warning signs [O.R. = 3.27, 95% C.I. = (2.32, 4.61)]; and, 5) planful coping [O.R. = 2.01, 95% C.I. = (1.49, 2.72)]. Significant predictors of adherence to long-term pharmacotherapy were: favorable attitudes toward antidepressant treatment [OR = 2.20, 95% CI = (1.50, 3.22)], and increased confidence in managing medication side effects [OR = 1.10, 95% CI = (1.04, 1.68)]. Among primary care patients at high risk for depression relapse, enhanced attitudes towards antidepressant medicines and higher confidence in managing side effects were key factors associated with greater adherence to maintenance pharmacotherapy.