Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma whose cause is largely unknown. Reported risk factors include genetic alterations (e.g., p53 mutations, a defective gene at 1 lp15.5, or specific chromosomal translocation of t(2: 13)), and parents' use of drugs around the time of conception. We present results from a national, case-control study of 249 RMS cases (1 70 males and 79 females) and 302 controls (196 males and 106 females). The cases, aged 0-20 years at diagnosis, were identified via the Intergroup RMS Study-I11 during 1982Study-I11 during -1988. Controls were selected by random digit telephone dialing. As a supplement to the original study, information on genetic diseases and birth defects (BD) was collected from the subjects' parents by telephone interview. Fifty-six (22.5%) cases and 55 (18.2%) controls were reported to have genetic diseases or BD (odds ratio [OR] = 1.30,95% confidence interval [CI] = 0.85-2.02, P = .21). The case group had a significantly higher frequency of neurofibromatosis type I (NF1) than did the control group, i.e., five cases (2.0%) had NFl vs. zero controls ( P = .02). The case group also had a higher frequency of major BDs than did the control group (6.0% vs. 2.6%, OR = 2.36,95% CI = 0.92-6.52, P = .05). However, this excess was only observed in males (7.6% vs. 2.6%, OR = 3.16, 95% CI = 1.02-10.41, P = .02). Among the 15 cases having both RMS and major BDs, six (40.0%) had