Impairment of natural cytotoxicity mediated by natural killer (NK) cells may play a role in the pathogenesis of penile carcinoma. The aim of this study was to examine the NK activity profile and its prognostic significance in patients with squamous cell carcinoma of the penis. The NK activity was measured in peripheral blood mononuclear cells (PBMCs) from 39 patients diagnosed histologically as having invasive squamous cell penile carcinoma and 4 patients with verrucous carcinoma of the penis. Of 39 patients with invasive squamous cell carcinoma, 4 had undergone previous penile amputation. According to the prognosis, the patients with invasive squamous cell carcinoma were divided into two groups: with metastasis and without metastasis. The patients were evaluated in relation to clinicopathologic variables using univariate analyses. NK cell activity was significantly decreased in all patients with penile carcinoma when compared with the control groups (p < 0.0001). There was no statistically significant difference between the groups with and without metastasis. We conclude that there is a decrease in NK activity in PBMCs from patients with penile carcinoma and that the presence of advanced disease or metastatic involvement is not responsible for this reduction.