Nafcillin, which is selectively used for Methicillin-sensitive Staphylococcal Infections, is a penicillin family of antimicrobial agents with a narrow antimicrobial range, but is not frequently used in clinical practice. In addition, the side effects of Penicillin-based antimicrobials are not well known except hypersensitivity. However, several cases have been reported since Mohr JA et al. reported nafcillin-induced hypokalemia in 1979, and recently, FDA's Adverse Event Reporting System (FAERS) reported that nafcillin had a higher incidence of hypokalemia than oxacillin. In Korea, this is the first report that the authors investigated. Severe hypokalemia was detected in a 59-year-old male hospitalized for traumatic cerebral hemorrhage who received 2g of nafcillin per day for more than two weeks for methicillin-sensitive Staphylococcus epidermidis sepsis. Further examination and literature search confirmed the association with nafcillin and we report this case with a review of the literature.