Although it has not been demonstrated yet, phenytoin is expected to reduce efavirenz exposure through coinduction of cytochrome P450 (CYP) 3A4 and CYP2B6. Conversely, efavirenz has been shown in vitro to inhibit the enzymes responsible for phenytoin metabolism, CYP2C9 and CYP2C19. We report a case in which a potential bidirectional drug interaction between phenytoin and efavirenz resulted in lower-than-expected efavirenz concentrations and elevated phenytoin levels. Therapeutic drug monitoring was used in this case to ensure adequate efavirenz exposure.