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No previous studies have examined if genetic factors interacts in the relationship between occupational risk factors and hip and knee osteoarthritis (OA).To examine occupational risk factors for Hip and Knee OA leading to Total Joint Arthroplasty, and if gene-exposure interaction, affect the risk factor-outcome relationship.In October 2012 all twin pairs alive in the Danish Twin Register (DTR) with at least one in the pair registered in the Danish Hip or the Danish Knee Arthroplasty Registers (DHA/DKA) with a diagnosis of primary OA were sent a detailed questionnaire regarding previous occupation, related exposures and complementary environmental factors. The analyses included cumulated exposures, McNemar`s X2 tests, and conditional logistic regression including gene-exposure-interaction variables.1181 twins responded (rate 58.9%). Responder analyses did not display any significant difference with non-responders with respect to diagnosis, zygosity and sex. We found a gene-exposure effect modification in hip OA-lifting and lifting-walking with OR`s 17.7 (1.1–280.2) and 10.4 (1.00–107.1), respectively, and a clear dose-response relationship between hip OA and prolonged standing-walking. Significant occupational risk factor in knee OA was kneeling, but no gene-kneeling interaction was detectable.Gene-exposure effect modification may be important in the development of hip OA in particular exposures to lifting and lifting-walking, but not in knee OA.