Isotretinoin is the most efficacious long-lasting treatment for acne; however, some factors, including polycystic ovary syndrome (PCOS), patient age, family history, and type and number of acne lesions, may lead to treatment resistance or relapse following treatment. The aim of this study was to compare the efficacy and permanence of systemic isotretinoin (SI) in nodulocystic acne patients with and without PCOS and to evaluate the factors associated with relapse during the first and second post-treatment years. The study included 96 female patients with nodulocystic acne. SI 0.5-1 mg/kg/dl was given, with a total cumulative dose of 120-150 mg/kg. Response to treatment and relapse during the first and second post-treatment years were evaluated. In all, the 50 non-PCOS and 46 PCOS acne patients were similar. SI was similarly efficacious in both groups. In total, eight patients relapsed during the first post-treatment year, versus 16 during the second. Relapse during the first year was associated with the number of nodules at the start of treatment and the number of papulopustular lesions at the end of treatment, whereas PCOS, patient age, and the number of nodules at the start of treatment were associated relapse during the second year. Regardless of its association with PCOS, SI was effective in the treatment of nodulocystic acne. The factors associated with relapse during the 1(st) and 2(nd) post-treatment years differed, except for the number of nodules at the start of treatment.