Adverse reproductive outcomes among female health care workers have been reported, but previous studies have been of limited sample size. We evaluated self-reported occupational exposure to antineoplastic drugs, anesthetic gases, antiviral drugs, sterilizing agents, and X-rays and the risk of spontaneous abortion (SA) in U.S. nurses. Retrospective data on pregnancy outcome, occupational exposures, work schedule, and lifestyle factors were collected from 7,482 participants of the Nursesí Health Study II who worked as a nurse during the first trimester of pregnancy. The overall participation rate was 76%. Log binomial regression was used to estimate relative risks (RRs) and 95% confidence intervals (95% CI). Participants reported 6,707 live births and 775 (10%) SAs (< 20 weeks gestation), 74% of occurred before the 12th week of pregnancy. After adjusting for age, parity, shift work, and hours worked per week, reported exposure to antineoplastic drugs was associated with an increased risk of SA (RR = 1.86, 95% CI = 1.27-2.73); particularly with early SA of < 12 weeks gestation (RR = 2.04, 95% CI = 1.33-3.13). Reported exposure to sterilizing agents was associated with a 2-fold increased risk of late SA (12-20 weeks) (95% CI = 1.28-3.93), but not with early SA. There was a suggested increase in risk of early SA with X-ray exposure (1.29; 0.99-1.68). Antiviral drug and anesthetic gas exposures were not associated with SA in our study. This study suggests that occupational exposures to antineoplastic drugs and sterilizing agents are related to an increased risk of SA.