Disease diagnosis and poor quality of life has been suggested as a "teachable moment" that facilitates smoking cessation, yet many patients continue to smoke. One reason for this inconsistency may be the potential moderating role of depressed mood. This study prospectively examined the role of depressed mood on the relationship between physical quality of life (PQoL) and smoking cessation among medically ill smokers. We hypothesized that poorer PQoL will be associated with smoking cessation, but only among those with little to no depressed mood. Nurses delivered smoking cessation counseling to medically ill patients (N = 273) who continued to smoke despite past hospitalization. Participants were assessed at baseline and at 2, 6, and 12-months later. The interaction between PQoL and depressed mood significantly predicted 1) 7-day point prevalence abstinence rates at both 2 and 12 months post-treatment [2 months: adjusted OR = 1.005, 95%CI 1.001-1.009, p < .05; 12 months: adjusted OR = 1.007, 95%CI 1.002-1.011, p < .005)] and 2) continuous abstinence rates at both 2 and 12 months post-treatment [2 months: adjusted OR = 1.011, 95%CI 1.004-1.019, p < .005; 12 months: adjusted OR = 1.006, 95%CI 1.001-1.011, p < .05] even after controlling for important covariates. The odds of quitting smoking increased for every one-unit decrease in PQoL, but only among those with little to no depressed mood. Medically ill smokers with poor quality of life may need more intensive smoking cessation interventions that include mood management to help them quit smoking.