Drug-induced aseptic meningitis is a known but rare adverse reaction to some medications including nonsteroidal antiinflammatory, antiepileptic, antimicrobial, and immune modulating medications. Of the antimicrobial medications causing aseptic meningitis, trimethoprim-sulfamethoxazole (TMP/SMX) is the most frequently cited cause in the literature. It has been reported to primarily affect women and patients with immune dysfunction. We report a case of a healthy 52-year-old man, the youngest adult male with TMP/ SMX-induced aseptic meningitis reported in the United States. The patient presented with rapidly progressive neurologic decline requiring intensive care unit-level admission, followed by rapid recovery when TMP/SMX was withheld. Cerebrospinal fluid analysis was consistent with aseptic meningitis. Further testing for herpes simplex virus, HIV, cryptococcus, Lyme disease, blastomyces, histoplasma, lymphocytic choriomeningitis, coccidioides, enterovirus, syphilis, methicillin-resistant Staphylococcus aureus, and streptococcus were all negative. The patient made a full recovery. This report highlights the presentation and management of a rare reaction to TMP/SMX. In addition to a thorough evaluation for infectious meningitides, physicians should recall medications causing meningitis, including TMP/SMX.