Drugs known to affect the red blood cell membrane and used clinically in neonates were tested for their ability to cause increased14C-bilirubin uptake by erythrocyte ghosts. The additional uptake of bilirubin by ghosts in the presence of penicillin G, phenobarbital, furosemide and theophylline may be explained by the effect of these drugs on free bilirubin levels as measured with a horseradish peroxidase assay. In contrast, the effect of chlorpromazine in causing increased bilirubin uptake by ghosts could not be totally explained by either ghost lysis or increased free bilirubin levels, as measured by light scattering, and was due to a direct effect of chlorpromazine on the ghost membrane. Our results demonstrate that drugs may act through different mechanisms in causing increased bilirubin uptake by erythrocytes.