Objective Fournier's gangrene is a necrotizing fasciitis that affects the perineal, genital, or perianal regions. The objective of this study was to highlight this uncommon condition with a particular focus on the disease course in females. Materials and methods From 1996 to 2008, we prospectively collected data from 38 patients with Fournier's gangrene (12 women, 26 men) and retrospectively analyzed relevant parameters. Results The mean age was 60.9±11.3 years for females (group I) and 56.2±11.7 years for males (group II). In both groups, the main predisposing factors were diabetes mellitus and obesity (body mass index of 30 or higher). Twelve men (46.2%), but no women, had chronic alcoholism. The most commonly isolated agents were Escherichia coli (n=22), streptococcal species (n=18), Pseudomonas aeruginosa (n=9), and Staphylococcus aureus (n=7). Mortality was significantly higher among females (50%) than males (7.7%; p=0.011). Peritonitis was present in seven group I patients (58.3%) and in two group II patients (7.7%). The retroperitoneum was involved in seven female patients (58.3%) and four male patients (15.4%). Conclusion The female gender is a risk factor for mortality in patients with Fournier's gangrene and is associated with a higher incidence of inflammation of the retroperitoneal space and abdominal cavity. Differences in male and female genital anatomy may be the reason for the rapid spread of infection to the retroperitoneum and the fatal outcome in women. Fournier's gangrene as a high-risk disease in females should attract exceeding attention.