The role of human papillomavirus (HPV) infection and other reported cofactors in the genesis, evolution, and clinical manifestations of precancerous and cancerous squamous cell lesions of the penis were studied in 34 men. Clinically, all lesions demonstrated aceto-whitening. Histologic changes of HPV infection formed a field-of-change that involved the components of the preputial cavity in all patients. These changes were associated with minor grades of penile intraepithelial neoplasia (PIN I and II) in 19 patients, major grades of PIN/carcinoma in situ (PIN III/Tis) in 7, and invasive squamous cell carcinoma (SCCa, Stages T2 and T3) in 8. Most of the patients (79.4%) were heavy smokers; 52.9 percent had a history of HPV infection, PIN, or invasive penile SCCa; and 60 percent of 30 patients had female sexual partners who had HPV-related genital neoplasia. A pilot virologic study of specimens obtained from 20 representative patients utilizing polymerase chain reaction amplification detected HPV DNA in 80 percent. Laser therapy was aimed at the entire field-of-change in 30 patients; recurrent minor-grade PIN or SCCa developed in 2 of 23 patients (8.7%) followed for up to three years. Of the 4 remaining patients treated with local excision or partial penectomy, 3 (75%) had development of recurrent minor-grade PIN when followed for up to four years. The combination of the host of carcinogenic factors and currently rampant immunologic disorders will likely lead to an increase in the historically low incidence of SCCa of the penis in the United States.