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Background Depressive symptoms are prevalent during pregnancy and the postpartum period and affect risk for smoking relapse. Whether and how depression affects response to postpartum interventions designed to sustain smoking abstinence is unknown. Purpose We examined end-of-pregnancy depressive symptoms as a moderator of response to two postpartum-adapted smoking relapse prevention interventions. Methods Women (N = 300) who quit smoking during pregnancy were randomized to receive either a postpartum intervention focused on psychosocial factors linked to postpartum smoking (Strategies to Avoid Returning to Smoking [STARTS]) or an attention-controlled comparison intervention (SUPPORT). Women completed the Edinburgh Postnatal Depression Scale at the end of pregnancy. Smoking status was biochemically assessed at the end of pregnancy and at 12, 24, and 52 weeks postpartum. Results End-of-pregnancy depressive symptoms moderated response to postpartum smoking relapse prevention interventions (χ 2 = 10.18, p =.001). After controlling for variables previously linked to postpartum smoking relapse, women with clinically significant end-of-pregnancy depressive symptoms (20%) were more likely to sustain abstinence through 52 weeks postpartum if they received STARTS. In contrast, women with few end-of-pregnancy depressive symptoms were more likely to sustain abstinence through 52 weeks postpartum if they received SUPPORT. Changes in the psychosocial factors addressed in the STARTS intervention did not mediate this moderation effect. Conclusion Assessment of end-of-pregnancy depressive symptoms may help determine success following postpartum smoking relapse prevention interventions. Women with elevated end-of-pregnancy depressive symptoms benefited from postpartum relapse prevention intervention tailored to their psychosocial needs, while those with few symptoms were more successful in postpartum intervention that used standard behavioral components. Clinical Trial Registration NCT00757068. [ABSTRACT FROM AUTHOR]