Primary cultures of intact, functional heptocytes were used to compare the relative toxicity of four nonsteroid antiinflammatory agents (NSAID)--benoxaprofen, orpanoxin, aspirin, and ibuprofen--with that of indomethacin. The relative toxicity of these compounds was evaluated on the basis of the release of lactate dehydrogenase, levels of urea (an indicator of a liver specific function), viability (based on dye exclusion), and morphology after a 12-h exposure to concentrations ranging from 0 to 1000 microM. Evaluation of the data obtained from these three parameters enabled us to rank these compounds from toxic to nontoxic, in decreasing order to toxicity: indomethacin greater than benoxaprofen greater than ibuprofen greater than or equal to aspirin greater than or equal to orpanoxin. Morphological evaluations of hepatocytes exposed to these agents under the same conditions supported the order of ranking for these compounds. Ultrastructurally, cells exposed to the two highest concentrations of indomethacin were severely damaged, as evidenced by marked cellular necrosis, nuclear pleomorphism, margination, swollen mitochondria, reductions in the number of microvilli, smooth endoplasmic reticulum proliferation, and cytoplasmic vacuolation. In comparison, exposure of hepatocytes to the highest dose of orpanoxin resulted only in increased vacuolation, a slight increase in cellular debris, and increased electron density of the cytoplasm of hepatocytes.