OBJECTIVE: We aimed to determine the association of physical activity and dietary factors on RA risk. METHODS: This case-control study within the Mayo Clinic Biobank matched incident RA cases (two codes plus disease-modifying anti-rheumatic drug, PPV 95%) to controls 1:3 on age, sex, and recruitment year/location. A baseline questionnaire assessed activity and dietary exposures. Logistic regression models calculated adjusted odds ratios (aOR) with 95% confidence intervals (CI) of RA for each of 45 activity/dietary exposures. RESULTS: We identified 212 incident RA cases and 636 controls (mean age 64, 70% female). Active work physical activity was associated with elevated risk of RA (aOR 3.00, 95% CI 1.58-5.69 vs. sedentary); leisure activity was not (aOR 0.96, 95% CI 0.64-1.42 sedentary vs. active). Three or more servings high-fat food and 5+ servings fruits/vegetables daily showed non-significant associations with RA (aOR 1.22, 95% CI 0.74-2.00 vs. 0-1 time; aOR 0.75, 95% CI 0.51-1.11 vs. 0-3 times), especially in sensitivity analyses with at least five years between questionnaire and RA (aOR 1.80, 95% CI 0.69-4.71; aOR 0.54, 95% CI 0.27-1.08). Alcohol binging was not associated with RA risk (aOR 1.28, 95% CI 0.56-2.96). Finally, sensitivity (versus primary) analyses showed a nonsignificant increase in RA risk for most vitamins and supplements. CONCLUSION: Active work physical activity and some nutritional profiles (increased high-fat, reduced fruit/vegetable consumption) may be associated with increased risk of RA. Confirmatory studies are needed.