OBJECTIVE To identify associations between cocaine exposure during pregnancy and medical conditions in newborn infants from birth through hospital discharge. METHODS Multisite, prospective, randomized study. METHODS Brown University, University of Miami, University of Tennessee (Memphis), and Wayne State University. Subjects A total of 717 cocaine-exposed infants and 7442 nonexposed infants. METHODS Results of physical examination and conditions observed during hospitalization. RESULTS Cocaine-exposed infants were about 1.2 weeks younger, weighed 536 g less, measured 2.6 cm shorter, and had head circumference 1.5 cm smaller than nonexposed infants (all P<.001). Results did not confirm previously reported abnormalities. Central and autonomic nervous system symptoms were more frequent in the exposed group: jittery/tremors (adjusted odds ratio, 2.17; 99% confidence interval, 1.44-3.29), high-pitched cry (2.44; 1.06-5.66), irritability (1.81; 1.18-2.80), excessive suck (3.58; 1.63-7.88), hyperalertness (7.78; 1.72-35.06), and autonomic instability (2.64; 1.17-5.95). No differences were detected in organ systems by ultrasound examination. Exposed infants had more infections (3.09; 1.76-5.45), including hepatitis (13.46; 7.46-24.29), syphilis (8.84; 3.74-20.88), and human immunodeficiency virus exposure (12.37; 2.20-69.51); were less often breastfed (0.26; 0.15-0.44); had more child protective services referrals (48.92; 28.77-83.20); and were more often not living with their biological mother (18.70; 10.53-33.20). CONCLUSIONS Central and autonomic nervous system symptoms were more frequent in the exposed cohort and persisted in an adjusted analysis. They were usually transient and may be a true cocaine effect. Abnormal anatomic outcomes previously reported were not confirmed. Increased infections, particularly sexually transmitted diseases, pose a serious public health challenge. Exposure increased involvement of child protective services and out-of-home placement.