OBJECTIVE To review four cases of combined hepatic and renal toxicity that may be associated with the administration of nafcillin in adults. This type of adverse event with the use of nafcillin has not been previously documented in the literature. METHODS References from pertinent articles are identified throughout the text. RESULTS Nafcillin is a widely used penicillinase-resistant penicillin. In four patients receiving nafcillin doses greater than 9 g/24 hours, changes in renal and hepatic function markers were noted within 72 hours of the initiation of nafcillin therapy. Laboratory values returned toward baseline when nafcillin therapy was discontinued. Elevations in blood urea nitrogen, creatinine, total bilirubin, and lactate dehydrogenase have been previously described in the literature for penicillin-like agents other than nafcillin. The exact mechanism for such toxicities as well as patient risk factors have not been clearly established. CONCLUSIONS Caution should be taken when initiating nafcillin therapy. Evaluation of renal and liver function tests prior to initiating nafcillin therapy and within the first 72 hours appears warranted. If hepatic and/or renal toxicity is observed, discontinuation of nafcillin should be considered.