To evaluate the effect of prenatal polydrug exposure on infant attention, 105 8-week-old African-American infants were presented a series of stimuli and their heart rates (HRs) were recorded. Infants were identified postnatally based on mothers' substance use. Four groups were tested: 1) preterm drug-exposed infants (n = 25); 2) full-term, drug-exposed (n = 32); 3) preterm nonexposed (n = 22); and 4) full-term, nonexposed (n = 26). Preterm infants' ages were corrected. Infant's baseline HRs were recorded and then stimuli presented in the following order: auditory (rattle), visual (red ring), and social (examiner's face and voice). There were no HR differences at baseline or in auditory or visual conditions. However, significant differences (F(2, 103) = 6.54, p < 0.01) were seen in response to social stimuli. Drug-exposed infants showed an acceleratory HR indicating distress or arousal and control infants showed a deceleratory response indicating focused attention and there was an interaction due to greater HR response in preterms. Hierarchical regression indicated cocaine (R2 = 0.034, p < 0.05) but not other drug use and instability in parenting (R2 = 0.137, p < 0.001) accounted for the observed differences.