To evaluate the efficacy of hydroxychloroquine (HCQ) and quinacrine (Qn) association, at two different dosages, in treatment of lupus skin lesions not responding to HCQ alone. Thirty-four patients, affected by cutaneous and systemic lupus erythematosus, were retrospectively analysed. They were treated by HCQ (5 mg/Kg/qd) and Qn with two regimens: 100 mg/qd (29 cases) and 50 mg/qd (5 cases). Discoid lupus erythematosus (19 cases), acute malar rash (6 cases), chilblain lupus (4 cases) showed a significant improvement with combination therapy (P = 0.009, P = 0.019, and P = 0.04, respectively). Ten patients with subacute cutaneous lupus showed a partial response, whereas lupus profundus didn't improve. The same overall response rate was recorded comparing two Qn regimens, but subjects taking 100 mg/qd improved more rapidly than the others (P = 0.001). Ten patients developed side effects, mainly represented by skin yellowish discolouration. Depression and severe headache with nausea, which were globally recorded in two cases, led to drug withdrawal. One additional case of hepatitis was recorded in a patient with preexisting Hepatitis C virus (HCV) infection. Combination of HCQ and Qn is rapidly effective at 100 mg/qd and well tolerated in the treatment of lupus skin lesions unresponsive to HCQ alone.