The purpose of this article is to familiarize physicians with the risks of prescribing trimethoprim/sulfamethoxazole (TMP/SMX) for patients who have kidney or cardiac pathology, have hyperkalemia, or take other interacting medications. Although TMP/SMX is a drug that is frequently used to treat skin and soft-tissue infections of the leg and foot, particularly if methicillin-resistant Staphylococcus aureus is identified, it is not an innocuous antibiotic. Literature documenting the many adverse effects of TMP/SMX is reviewed. A case history is presented illustrating the association of TMP/SMX with the development of a life-threatening situation. Ways of avoiding these adverse events are discussed, and the use of safer antibiotics is recommended.