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OBJECTIVE: To systematically study the association of monoclonal gammopathy of undetermined significance (MGUS) with all diseases in a population-based cohort of 17,398 patients, all of whom were uniformly tested for the presence or absence of MGUS. PATIENTS AND METHODS: Serum samples were obtained from 77% (21,463) of the 28,038 enumerated residents in Olmsted County, Minnesota. Informed consent was obtained from patients to study 17,398 samples. Among 17,398 samples tested, 605 cases of MGUS and 16,793 negative controls were identified. The computerized Mayo Medical index was used to obtain information on all diagnoses entered between January 1, 1975, and May 31, 2006, for a total of 422,663 person-years of observations. To identify and confirm previously reported associations, these diagnostic codes were analyzed using stratified Poisson regression, adjusting for age, sex, and total person-years of observation. RESULTS: We confirmed a significant association In 14 (19%) of 75 previously reported disease associations with MGUS, Including vertebral and hip fractures and osteoporosis. Systematic analysis of all 16,062 diagnostic disease codes found additional previously unreported associations, including mycobacterium infection and superficial thrombophlebitis. CONCLUSION: These results have major implications both for confirmed associations and for 61 diseases in which the association with MGUS is likely coincidental. [ABSTRACT FROM AUTHOR]