A retrospective case-control study investigated 45 Missouri outpatients with annular rashes meeting a surveillance case definition for erythema migrans and with onset in 1990-1991. Risk factors included being male, living near a body of water, and hunting. Twenty patients (44%) associated their rash with the bite of a tick; of these, 5 described an adult Amblyomma americanum. A typical rash was described as expanding over time and measuring 8 cm in diameter at 4 days after onset. Mild constitutional symptoms were common but fever was uncommon. Serologic tests failed to incriminate Borrelia burgdorferi or selected other arthropodborne pathogens. Skin specimens from suspected erythema migrans lesions of 23 Missouri patients sampled prospectively in 1991-1993 were culture-negative for B. burgdorferi. Thus, tick bite-associated annular rashes in Missouri remain idiopathic. Possible causes include infection with a novel A. americanum-transmitted pathogen and an atypical toxic or immunologic reaction to tick-associated proteins.