Four patients with squamous cell carcinoma of the perineal region were diagnosed and treated during the last 4 years in our institutions. The underlying diagnoses consisted of recurrent pilonidal disease, Crohn's disease, and hidradenitis suppurativa. In all patients, a pattern of a long-term inflammatory process was evident. Current concepts regarding the pathophysiology of a chronic inflammatory state and malignant transformation are reviewed. We conclude that regardless of the original pathology, all chronic inflammatory processes in the perineal region should be evaluated for malignant degeneration. A high index of suspicion may potentiate an early diagnosis, possibly improving the chance of cure.