Although most human papillomavirus infections can be managed satisfactorily by office methods, extensive, refractory, and dysplastic vulvar disease poses frustrating problems. This observational cohort study evaluated the efficacy of extended laser ablation (vaporization of both clinically apparent and adjacent subclinical changes) among 160 women drawn from 1000 referrals between 1982-1987. During the final 2 years, the protocol incorporated two different 5-fluorouracil (5-FU) regimens: routine once-weekly applications as prophylaxis against postoperative recurrence, and twice-weekly dosing to avoid further laser surgery among patients with early but diffuse failures. One hundred seven patients (66.9%) were controlled by a single operation. Subsequent therapy for the remaining 53 women involved 44 additional superficial photovaporizations, 38 courses of therapeutic 5-FU, four deep laser destructions with skin grafting, and six trials of systemic alpha-interferon. Eventually, 158 patients (98.7%) entered stable clinical remission. Adjuvant 5-FU improved success rates among the 76 women with two or more adverse prognostic factors (87.5 versus 55.8%; P less than .01) but had no prophylactic value in the other 84 women. In contrast, the therapeutic 5-FU regimen was generally effective, avoiding the need for further surgery in 22 (57.9%) of 38 inevitable failures, compared with only four successes (10.3%) among 39 historic controls managed with caustic agents (chi 2 = 19.5; P less than .001). Improvements in laser technology had no impact upon outcome, but more sophisticated heat containment strategies reduced postoperative pain, healing time, and morbidity. Given adequate technique and an appropriate indication, we find extended laser ablation to be an excellent primary control method. However, the availability of an effective adjuvant regimen would be a valuable complement.