Studies investigating antenatal caffeine consumption and reproductive outcomes show conflicting results, and most studies have used maternal self-reported caffeine consumption to estimate fetal exposure. This study (n=1,606) was specifically designed to test the association of caffeine and its primary metabolites in umbilical cord blood with intrauterine growth restriction (IUGR). Pregnant women were recruited from 56 obstetric practices and 15 clinics affiliated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000. In an adjusted model including caffeine only, levels in all quartiles were associated with reduced risk of IUGR. In adjusted analyses including paraxanthine and caffeine, serum paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective. These conflicting findings suggest that cytochrome P-450 1A2 (CYP1A2) metabolic activity may be associated with IUGR, so the ratio of paraxanthine to caffeine was then modeled. The likelihood of IUGR increased 21% for every one standard deviation change in the ratio (adjusted odds ratio=1.21, 95% confidence interval: 1.07, 1.37), suggesting that CYP1A2 activity, and not the absolute levels of paraxanthine, influences fetal growth. No associations were observed between caffeine or any metabolites and preterm delivery.