There have been occasional reports of patients with refractory cutaneous lupus improving after cessation of cigarette smoking. It has been hypothesized that the effects of cigarette smoking on hepatic cytochrome P450 induction can alter the metabolism of antimalarials. Our objective was to determine the role of smoking in the efficacy of antimalarial therapy in cutaneous lupus. A retrospective cohort study from the University of Toronto Lupus Clinic. Patients with either acute discoid or subacute cutaneous lupus (SACL) who received antimalarial therapy for their cutaneous lesions were selected. The smoking group consisted of regular smokers, while the nonsmoking group consisted of individuals who never smoked during the study period. The primary outcome measure was the complete resolution of the cutaneous lesion at 6 and 12 months of antimalarial therapy. Secondary outcome measures included the mean steroid dose and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Analysis included descriptive statistics and Fisher's exact test. Seventeen smokers (9 with discoid lupus, 5 SACL, 3 both) and 19 nonsmokers (11 discoid, 6 SACL, 2 both) were identified. The cutaneous eruption resolved completely in 3/17 smokers versus 9/17 nonsmokers after 6 months of antimalarial therapy (p < 0.035) and 3/16 smokers and 9/17 nonsmokers at 12 months (p < 0.046). There was no significant change in the mean steroid dose or SLEDAI in either group. Smoking appears to decrease the efficacy of antimalarial therapy in cutaneous lupus. The interaction between smoking and the efficacy of antimalarials in a variety of SLE presentations should be investigated further.