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An outbreak of tick-borne relapsing fever (TBRF) originating at the North Rim of Grand Canyon National Park was investigated in 1990. To determine risk factors for the disease, almost 7,000 parties of visitors were surveyed; over half responded, representing > 10,000 people. Fifteen cases of confirmed or probable TBRF were identified in visitors and 2 in employees. All patients except one experienced symptoms after overnight stays in a group of cabins that had not been rodent-proofed after a TBRF outbreak in 1973 (relative risk for visitors [RR] 8.2, 95% confidence interval [CI] 1.1-62). Seven cases of TBRF were associated with a single cabin (RR 98, 95% CI 30-219). Structural flaws and rodent nests were common in the implicated cabins and rare in unaffected cabins. This investigation suggests that measures to rodent-proof cabins at sites where TBRF is endemic prevent reinfestation of cabins by infected rodents and tick vectors, thereby preventing the spread of disease in humans.