As part of a multicenter study of prenatal cocaine and/or opiate (COC-OP) exposure and child outcome, 4 clinical centers (Brown Univ., Univ. of Miami, Univ. of Tennessee, Memphis and Wayne State Univ.) enrolled 1334 infants at 1 month of age in a longitudinal protocol. The sample included 628 infants exposed (EXP) to cocaine and/or opiates based on maternal report or meconium assay and 705 comparison (COMP) infants with no cocaine/opiate exposure matched by gestational age, race and gender. Background exposure to alcohol, marijuana and tobacco occurred in both groups. The sample was divided into 3 birthweight groups; N=149 VLBW<1500 gm, N=402 LBW, 1501-2500 gm and N=782, Term, > 2500 gm. The mothers were >18 years old and mostly Black, single and on Medicaid. Neurobehavioral measures included the NICU Network Neurobehavioral Scale (NNNS), acoustical cry analysis and auditory brain response (ABR). Data was analyzed using 2 (Exposure) × 3 (Birthweight group) ANOVA. On the NNNS, EXP scores lower than COMP on state, P<.03. The interaction showed the lowest scores in the VLBW EXP group, P<.04. Birthweight effects were found on handling, P<.05, hypertonia, P<.001, quality of movement, P<.001, low arousal, P<.03, reflexes, P<.004, and on the stress/abstinence scale, P<.001. An interaction showed more reflex asymmetries in the LBW EXP group, P<.05. On the cry, there were effects of EXP, P<.02, birthweight, P<.01 and the interaction P<.05 on the number of short utterances. Birthweight effects were found on the number of cry utterances, P<.001, latency to cry onset, P<.008, duration of first cry, P<.01, mean duration of cry utterance, P<.02, mean interval between cries, P<.001, and mean second resonance frequency, P<.001. There was an interaction effect on length of inspiration following first cry, P<.05. The ABR showed birthweight effects at 70 dB on peak 1, P<.008, and on the peak 1-3 latency, P<.01. Results show few effects for EXP but consistent effects for birthweight and support current findings that the effects of cocaine are more subtle than originally expected. This is the largest study of low and normal birthweight infants evaluating effects of cocaine/opiate use during pregnancy on infant outcome against a background of polydrug use.