Our aim was to evaluate whether serum concentrations of squamous cell carcinoma antigen (SCC-Ag) are an independent prognostic factor in patients with vulvar cancer. We measured SCC-Ag in pretreatment serum samples of 55 patients with squamous cell vulvar cancer, 30 patients with vulvar intraepithelial neoplasia (VIN) grade III and 50 healthy female controls. The results were compared with clinical data. Median serum concentrations of SCC-Ag in healthy female controls, patients with VIN III, and patients with invasive vulvar cancer were 0.5 (range 0.1 to 3.8) ng/mL, 0.5 (range 0 to 4.1) ng/mL and 1.6 (range 0.3 to 65) ng/mL, respectively (Mann-Whitney U test, p < 0.001). The 75% quantile of serum concentrations of SCC-Ag in patients with vulvar cancer was defined as cut-off level. Elevated pretreatment serum concentrations of SCC-Ag were significantly correlated with a shorter disease-free and overall survival (log-rank test, p=0.002; and p<0.001, respectively). A multivariate Cox regression model showed that serum concentrations of SCC-Ag are a prognostic factor of disease-free and overall survival independent of tumour stage (multivariate Cox regression model, p=0.03; and p=0.048, respectively). Pre-treatment serum concentrations of SCC-Ag were not correlated with tumour stage, histological grade and patients' age. In summary, our data indicate that serum concentrations of SCC-Ag may be an additional independent prognostic factor of disease-free and overall survival in patients with vulvar cancer.