There is little knowledge about how emotion regulation difficulties interplay with psychopathology in terms of smoking cessation. Participants (n = 250; 53.2 % female, M age = 39.5, SD = 13.85) were community-recruited daily smokers (≥8 cigarettes per day) who self-reported motivation to quit smoking; 38.8 % of the sample met criteria for a current (past 12-month) psychological disorder. Emotion regulation deficits were assessed pre-quit using the Difficulties with Emotion Regulation Scale (DERS; Gratz and Roemer in J Psychopathol Behav Assess 26(1):41–54, 2004) and smoking behavior in the 28 days post-quit was assessed using the Timeline Follow-Back (TLFB; Sobell and Sobell in Measuring alcohol consumption: psychosocial and biochemical methods. Humana Press, Totowa, 1992). A Cox proportional-hazard regression analysis was used to model the effects of past-year psychopathology, DERS (total score), and their interaction, in terms of time to lapse post-quit day. After adjusting for the effects of gender, age, pre-quit level of nicotine dependence, and treatment condition, the model revealed a non-significant effect of past-year psychopathology (OR = 1.14, CI 95 % = 0.82–1.61) and difficulties with emotion regulation (OR = 1.01, CI 95 % = 1.00–1.01) on likelihood of lapse rate. However, the interactive effect of psychopathology status and difficulties with emotion regulation was significant (OR = 0.98, CI 95 % = 0.97–0.99). Specifically, there was a significant conditional effect of psychopathology status on lapse rate likelihood at low, but not high, levels of emotion regulation difficulties. Plots of the cumulative survival functions indicated that for smokers without a past-year psychological disorder, those with lower DERS scores relative to elevated DERS scores had significantly lower likelihood of early smoking lapse, whereas for smokers with past-year psychopathology, DERS scores did not differentially impact lapse rate likelihood. Smokers with emotion regulation difficulties may have challenges quitting, and not having such difficulties, especially without psychopathology, decreases the potential likelihood of early lapse.