Objective: To describe neurodevelopment and head growth in HIV-1–infected and exposed uninfected infants with and without in utero exposure to opiates and cocaine. Methods: Using data from a multicenter cohort study of HIV-1–infected women and their children, the authors fit repeated measures regression models to estimate the effects of HIV-1 infection and in utero hard drug exposure on head circumference and Bayley Scales of Infant Development standard scores during the first 30 months. Results: Of the 1,094 infants included in the analysis, 147 (13%) were HIV-1–positive and 383 (35%) were exposed in utero to opiates or cocaine (drug-positive). Mean 4- month Bayley mental scores were lower in infants with only HIV-1 positivity (HIV-positive and drug-negative) (-8.2 points, p < 0.0001) or only drug exposure (HIV-negative and drug-positive) (−4.4 points, p = 0.0001) and tended to be lower in infants with both factors (HIV-positive and drug-positive) (−3.7 points, p = 0.0596), compared with those who were HIV-1-negative and not drug exposed (HIV-negative and drug-negative). However, by 24 months of age, there was no longer a decrement among HIV-negative and drug-positive infants, whereas HIV-1 infection was still associated with a decrement relative to uninfected infants. Similar results were seen for Bayley motor scores and for head circumference Z scores. Conclusions: HIV-1 infection and in utero opiate and cocaine exposure decrease birth head circumference and slow neurodevelopment at 4 months. At 24 months of age, however, only HIV-1 infection is associated with decreased neurodevelopment and head circumference. There may be some postnatal recovery from the effects of in utero hard drug exposure. Importantly, the detrimental effects of HIV-1 positivity and maternal hard drug use on neurodevelopment at 4 months are not additive, although they are additive for birth head circumference.