Familial clustering of pleural mesothelioma (PM) has been previously reported suggesting that genetic factors (predisposition) may be involved in PM. We studied parental cancer history in a cohort of 39 cases of PM and 259 age matched controls to assess the possible influence of family history on PM risk. Cases consisted of 39 patients with PM treated at our institution between 1978 and 1993. An age frequency matched control group (by 5-year age groups) consisted of 259 subjects who were spouses or friends of patients undergoing resection of primary lung cancer. Data were obtained by interview of controls and interview of the patient or next of kin (usually spouse) for cases. The following data were obtained using a standard questionnaire and medical record review; age, sex, date of diagnosis, history of asbestos exposure, smoking history, method of diagnosis, histologic subtype, type of treatment, parental cancer history and tumor type. Cases and control frequency of parental cancer and site specific tumor frequency were compared using chi-square analysis. Twenty-eight (71%) cases reported a parental history of cancer versus 114 (44%) in the control group (P<0.01). Gastrointestinal malignancies were the predominant tumor type among parents of cases, i.e. 11 cases (40%) versus 25% of controls (P<0.01). No other tumor site showed an increased frequency among cases. These data suggest a possible role for family history in the development of PM. Genetic predisposition may be important in the etiology of this tumor.