The relationship between major depressive disorder (MDD), treatment modality, and mood was evaluated in smokers participating in cessation programs. Participants (N = 549, 53.7% women, 46.3% men, 28% endorsing past MDD episodes) were randomly assigned to a cognitive-behavioral treatment (CBT) or health education (HE) intervention. Participants with a history of recurrent MDD (MDD-R) had higher rates of abstinence in CBT compared with HE even when the contribution of mood and the interaction between mood and an MDD x Treatment variable were included in the model. Likewise, higher levels of mood disturbance were reported by MDD-R smokers compared with those reporting a single episode. The study replicated results reported by R. A. Brown et al. (2001) and expanded upon them by evaluating the differential contribution of poor mood on cessation outcomes relative to MDD history.