Introduction: Statin therapy and obesity are associated with increased risk of developing type 2 diabetes mellitus (T2DM). Conversely, cardiorespiratory fitness (CRF) is inversely related to T2DM incidence. The interaction between statin therapy, obesity, and CRF has not been addressed. Hypothesis: Obesity and statins will be associated with increased risk of T2DM, while CRF will mitigate this increased risk. Methods: From the ETHOS cohort, we identified 570, 054 patients (age 60.7±10.1 years) with no T2DM. All completed a standardized exercise treadmill test (ETT) with no evidence of ischemia. Subsequently, 322,805 (56.6%) were treated with statins for at least 8 months (mean 9.5±5.9 years) and 247,249 were not. Participants were classified based on body mass index (BMI) as normal weight (BMI<25.0 kg/m 2 ), overweight (BMI 25.0-29.9 kg/m 2 ), Obese-I (BMI 30.0-34.9 kg/m2), and Obese-II (BMI ≥35.0 kg/m 2 ). We established five CRF categories based on age-specific quintiles of peak metabolic equivalents achieved: Least-Fit (n=95,071); Low-Fit (n=133,404); Moderate-Fit (n=110,973); Fit (n=158,004) and High-Fit (n=72,602). Adjusted Cox proportional hazards models were constructed to evaluate the association between BMI, statin therapy and T2DM risk, and the interaction with CRF status. Results: During the follow-up period (median 10.3 years), 44,662 developed T2DM (7.4 events/1,000 person-years of observation). The risk of developing T2DM was 44% higher in those treated with statins [Hazard Ratio (HR) 1.44; 95% confidence interval (CI) 1.41-1.48)] compared to those not on statin therapy. The risk increased progressively with higher BMI levels and was nearly 3 times higher for those in the Obese-II category (HR 2.96, CI 2.85-3.06). When T2DM risk was assessed across CRF categories within BMI groups, we noted a progressive decline in T2DM risk with increased CRF regardless of statin therapy or BMI status. The adjusted risk was approximately 25% to 40% lower for those in the two highest CRF categories. Conclusions: Statin therapy and obesity were associated with increased risk of developing T2DM. This risk was mitigated significantly with increased CRF regardless of BMI status.