We have investigated the effect of a range of drugs (some commonly coadministered with zidovudine [ZDV] to human immunodeficiency virus-positive patients) on intracellular phosphorylation of ZDV by stimulated peripheral blood mononuclear cells, Molt 4 cells, and U937 cells in vitro. Of the drugs tested (azoles, antiviral agents, antibiotics, and anticancer agents), only doxorubicin and ribavirin caused inhibition of anabolite formation as measured by high-performance liquid chromatography. This in vitro approach may provide important leads to potential interactions at the phosphorylation level in patients with human immunodeficiency virus disease. It is reassuring that so many commonly administered drugs do not alter ZDV phosphorylation.