The basis for the clinical variation in response to lead exposure in children is not well understood. We studied selected children from a large lead screening program in whom elevation of red cell protoporphyrin concentration (a measure of inhibition of the enzyme ferrochelatase) was markedly above or below average for a given blood lead level. We then measured the activity of the enzyme amino levulinate dehydratase in 306 of these children, and found that ALA-d activity was lower in children with higher protoporphyrin elevation, independent of the effects of lead. This observation, coupled with reports in the literature of families with ALA-d deficiencies and elevated red cell protoporphyrin values, makes likely a genetic basis for some of the variation in susceptibility to lead. The mechanism by which the two effects are associated remains unknown.