In a randomized trial, this study compared the longitudinal outcome patterns of veterans (N = 66) with substance use disorders and major depressive disorder receiving standard pharmacotherapy and either 12-Step Facilitation Therapy (TSF) or disorder-specific Integrated Cognitive Behavioral Treatment (ICBT). Depression and substance use were assessed at intake, during and after treatment using the Hamilton Depression Rating Scale and the Time Line Follow Back. Reductions in depression during treatment were comparable between the two treatment groups; however, their posttreatment patterns were distinct. While ICBT participants evidenced a steady linear decline in depression through six months posttreatment, a quadratic trend characterized TSF participants, for whom depression declined during treatment, but increased throughout posttreatment follow-up. During treatment, TSF participants used substances less frequently relative to those in ICBT; however, reductions in substance use were more stable through six months posttreatment among those in ICBT relative toTSF. While both interventions produced improvement in depression and substance use during treatment, ICBT may yield more stable clinical outcomes once treatment ceases.