Mycoplasma species are one of nature's most abundant groups of microbes. These bacteria inhabit a wide diversity of insect, plant, and animal species, including humans. Certain mycoplasma species have been identified in blood-sucking arthropods, including Ixodes ticks. Frequent human exposure to this genus of ticks led us to explore the possibility of tick-mediated transmission of these bacteria. We evaluated 7 residents of central New Jersey who developed fatigue, musculoskeletal symptoms, and cognitive disturbance after tick attachment. All 7 of these patients lacked both serological evidence and erythema migrans skin lesions characteristic of Lyme disease. We were able to amplify and quantitate Mycoplasma fermentans-specific DNA from their peripheral blood lymphocytes. After antimicrobial therapy, symptoms subsided, and M. fermentans DNA could no longer be detected in their blood specimens. These findings suggest that a subset of disseminated M. fermentans infections may be a vector-mediated process in humans and should be considered in patients with puzzling musculoskeletal presentations.