Reports of drug effects on infants and mothers exposed during pregnancy are limited by single site, small number studies. A large, multi-site cohort of infants exposed (EXP) to cocaine/opiates (C/O) was prospectively compared to a non-cocaine/opiate exposed (NON) group at birth and at discharge from their initial hospitalization. Exposure was defined as admitted use or confirmed C/O metabolites in meconium using a central GC/MS assay. Of 19,079 mothers screened from May, 1993 to May, 1995 at 4 clinical centers (Brown U, U of Miami, U of Tenn, Memphis and Wayne State U.), 11,810 eligible mothers consented to participate, and 1185 (10%) infants were identified as EXP. The EXP cohort was, on average; 1 week younger by Ballard gestational age; 449 grams birthweight lighter; 2.3 cm shorter; and 1.3 cm smaller head circumference (all p.values < 0.01). Nine systems which included 62 components were assessed during the newborn physical exam. Previously reported abnormalities in the GI, GU, and cardiac systems were not confirmed. However, CNS, 2.1[1.8-2.4]; autonomic 1.7[1.4-2.0], and respiratory 1.4[1.1-1.7] findings were greater in the EXP group, (Odds Ratios [± 95% confidence limits]). EXP infants had more syphilis 10.1[7.7-13.1]; were more often admitted to an ICU 1.4 [1.3-1.7], or Intermediate Care nursery 1.7[1.5-2.0]. EXP infants had more in-hospital referrals to Child Protective Services 45.4[39.6-52.0] and were more frequently identified as being boarder babies 30.8[25.6-37.1]. These data suggest that prenatal substance exposure has more impact on social rather than medical outcomes and that adverse medical outcomes are less common than have been previously reported.