Abstract: Transmitted by the Lone Star tick, Ehrlichia chaffeensis is the obligate intracellular organism responsible for human monocytic ehrlichiosis. During the last several years, a small number of case reports have surfaced in the literature that suggest a direct relationship between trimethoprim-sulfamethoxazole (TMP-SMX) use and the degree of morbidity in acute ehrlichiosis. In this article, we describe a patient who presented in the month of June to a small hospital in Delaware with overwhelming sepsis, toxic shock syndrome–like illness, after recent TMP-SMX use for a urinary tract infection. On transfer to our facility, our patient was treated promptly with doxycycline and improved significantly during the remainder of her stay. It is entirely possible that the severity of presentation seen in this case is related to this patient’s exposure to TMP-SMX in the setting of ehrlichiosis.