The ability to predict cancer progression may help the clinical management of patients with penile squamous cell carcinoma. We studied 22 cases of squamous cell carcinoma of the penis diagnosed between 1989 and 1998. The depth of invasion was measured from the basement membrane of the squamous epithelium to the deepest invasive cancer cells. Cancer progression was defined as the development of lymph node metastasis or distant metastasis. The mean patient age was 63 years and the mean follow-up was 28 months. Ten patients developed cancer progression. The mean depth of invasion among patients with cancer progression was 9.8 mM, as compared to the mean depth of invasion of 4.0 mM among those patients without cancer progression (P =.02). Vascular invasion was also predictive of cancer progression (P =.02). Metastases developed in the majority (6 out of 7) of cases invading more than 6 mM, but developed only in a minority (4 out of 15) of cases invading 6 mM or less. We conclude that depth of invasion and vascular invasion are significant predictors of cancer progression for penile squamous cell carcinoma.