Skillful laser ablation can remove any volume of human papillomavirus-associated vulvar disease but cannot prevent reactivation of the surrounding latent viral reservoir during postoperative healing. Conversely, interferon and 5-fluorouracil are relatively ineffective as primary therapies in clearing bulky lesions. In this study of 71 assessable patients, topical 5-fluorouracil and systemic interferon injections were used postoperatively. Success rates within the adjuvant 5-fluorouracil and laser alone arms were essentially the same (9 of 18 vs 8 of 20). In contrast, outcome in the interferon group was significantly better than that for the other two arms combined (27 of 33 [82%] vs 17 of 38 [45%]; chi 2 10.31; p less than 0.002). Moreover, 18 of 21 failures (86%) in the first two arms and 3 of 6 failures (50%) in the interferon arm were "rescued" from the need for a second laser surgical procedure by crossover to either the 1 or 3 MIU interferon regimen. Results from this open-label, randomized clinical trial suggest that even a relatively low dose of recombinant interferon, used in combination with effective surgical debulking, can markedly reduce the risk of postoperative recurrence.