We monitored the emergence of major depression (MDD) during treatment for nicotine dependence among 224 smokers. MDD was assessed on three occasions during the course of treatment with the mood disorders portion of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID), fourth edition (DSM-IV). Out of 224 participants, 20% had suffered a past episode of MDD, 18% of males and 22% of females. Four percent (n=10) experienced onset of MDD during the course of the study, four males and six females. Only 2 of the 10 cases managed to achieve abstinence at end of treatment. Those who reported large increases in depression symptoms between baseline and end of treatment (Week 10) were less likely to be abstinent at 26-week follow-up. The evidence indicates that those who treat nicotine dependence must be prepared to monitor and respond to the emergence of depression associated with treatment.