The hyperandrogenic-insulin-resistant acanthosis nigricans syndrome affects between 2% and 5% of hirsute women and is characterized by INS resistance, elevated INS levels, acanthosis nigricans, and androgen excess. These patients' response to therapy is unclear, although long-acting GnRH-a suppression has been proposed. The objective of this study was to determine the success of OC in suppressing the hyperandrogenemia of five patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome and the subsequent response to GnRH-a suppression of those women failing initial therapy. After 6 months of OC and SPA therapy, four patients experienced adequate suppression of free T. an increase in SHBG levels, and a subjective improvement in hair growth rate. Two also reported an improvement in hair texture. The total and free T levels in the fifth patient did not suppress after 8 months of OC therapy. Nevertheless, in this patient the administration of a GnRH-a along with hormonal replacement and SPA adequately suppressed free and total T, increased SHBG, and dramatically decreased the shaving interval. In conclusion, although GnRH-a suppression and hormonal replacement can be helpful in patients not responding to standard therapy, the majority of patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome will respond favorably to OC treatment. It is also clear that although hyperinsulinemia augments LH-stimulated androgen biosynthesis in vivo, it does not appear to be able to initiate or maintain androgen production in the absence of adequate gonadotropin stimulation.