Serious gram-positive infections present an increasingly common therapeutic dilemma. Combination antimicrobial regimens (e.g., linezolid with rifampin) aimed at improving bacterial eradication and preventing resistance are often used; however, most data supporting this treatment strategy are not from randomized controlled trials. We describe a patient with disseminated community-acquired methicillin-resistant Staphylococcus aureus infection who experienced a possible drug interaction between linezolid and rifampin that resulted in decreased serum linezolid levels. To our knowledge, this is the first published report of a possible drug interaction in a critically ill patient receiving concomitant linezolid and rifampin. Although we hypothesize that the reaction was caused by P-glycoprotein expression, further study is warranted.