The aim of this study was to investigate the relationship between history of selected diseases, genital traumas, and Peyronie's disease. A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Rome, where 134 men with Peyronie's disease and 134 male controls were interviewed. The association between Peyronie's disease and selected characteristics was estimated by means of odds ratios (OR) and 95% confidence intervals (CI). Patients who underwent invasive procedures on the penis (i.e., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16-fold increased risk for Peyronie's disease (OR = 16.1, 95% CI: 1.8-142), while a nearly three-fold increase was observed among patients who had genital and/or perineal traumatisms (95% CI: 1.0-7.1). A history of urethritis, uricacidemia, and lipoma was also significantly associated with an increased risk for Peyronie's disease. Twenty-one percent of the cases and none of the controls were affected by Dupuytren's contracture, and 4% of cases and none of the controls reported familial history for Peyronie's disease. The frequency of inflammatory or fibromatous lesions of the genital tract of the partner was significantly higher in men with Peyronie's disease than among controls. These results were consistent when performing a stratified analysis according to the type of controls (i.e., controls affected by urologic or by digestive conditions) to rule out the potential effect of recall bias. The findings of the study lend support to clinical reports stressing the importance of genital traumatisms and genetic conditions in the development of Peyronie's disease.