The long-term effects and tolerability of flutamide (Flu) in women with acne and seborrhea were evaluated. Over the 15-year period, which spans from January 1991 to January 2006, a total of 230 Caucasian women with acne, 211 of which also with seborrhea, received yearly reducing doses (250, 125, and 62.5 mg/day) of Flu alone or combined with oral contraceptive for a period varying from 3 to 6 years and more. Clinical and endocrine evaluations were performed half-yearly and yearly, respectively, in the first 3 years of the study, and yearly in the following years. Liver function evaluations were performed quarterly. Both the groups of patients under Flu therapy showed a similar, marked decrease in acne and seborrhea scores after 6 months of treatment compared with basal values. The maximum drug effect was observed after 1 year, and it was maintained during the following years of treatment. Androgens were strongly suppressed during treatment. During the first year of treatment with 250 mg/day, 4.8% of patients interrupted the study due to hepatic disorders. During the following years on the 125 and 62.5 mg/day doses, no transaminase elevation was observed. The study supports very low-dose Flu as a first-line therapy for women with acne and seborrhea.