Although infertility has been identified as an effect of chemotherapy for some cancer patients, the association of infertility with occupational exposure has not been investigated. This case-control study investigated the relationship of infertility with occupational handling of chemotherapy drugs by nurses and pharmacy personnel. Data were gathered by questionnaire from 4659 staff at facilities participating in the National Surgical Adjuvant Breast and Bowel Project collaborative clinical trials network of the National Cancer Institute. The 405 subjects reporting infertility were each matched by sex and age with three control subjects and compared for history of chemotherapeutic drug handling. Results for the total sample and for women showed a significantly elevated odds ratio (OR = 1.5; CI = 1.1 to 2.0) for self-reported infertility associated with occupational handling of chemotherapeutic drugs prior to onset of infertility. For men, the odds ratio was similar but not statistically significant. This worker population, with a mean age of 37, is in the prime of reproductive life. Prevention of chemotherapy side effects by use of available protection is preferable to risking infertility.