The objective of this study was to evaluate the efficacy of a risk factor-based drug screening program in a rural perinatal population with a low prevalence of substance abuse. The study was done at a university-based children's hospital in central Missouri. A risk factor-based meconium and infant urine drug screening program was compared to a universal meconium screening program in a newborn population over a 3 month period. Eighteen percent of the 462 deliveries met criteria for drug testing. Of those tested, 11/85 (12.9%) tested positive for marijuana (n 5 8) or cocaine (n 5 3), representing a detection rate of 2.4% of the total population. This compares well to the 2.6% detected in the universal testing protocol. In three patients, meconium analysis detected marijuana exposure, while urine analysis revealed no detectable drug. Risk factor-based meconium drug screening can identify most infants exposed to illicit drugs in rural perinatal populations with low baseline substance abuse rates. Meconium sampling is more likely than urine sampling to identify exposed infants.