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This cross-sectional observational study examined the degree to which cardiorespiratory fitness (CRF) and self-perceived stress are associated with cardiometabolic risk factors and the overall risk score for cardiovascular diseases. The second aim was to determine whether participants’ CRF levels moderate the relationships between stress and cardiometabolic risk.A gender-matched stratified sample (N = 197, 51% men, Mage = 39.2 yr) was used to ensure that participants with varying stress levels were equally represented. CRF was assessed with the Åstrand bicycle test, and perceived stress was assessed with a single-item question. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index (BMI), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glycated hemoglobin, and total cardiometabolic risk score (sum of the z-standardized residuals of the previously mentioned indicators) were assessed as outcomes.Higher LDL-C, TG, and total metabolic risk were found in participants with high stress scores (P < 0.05). In addition, lower SBP, DBP, BMI, LDL-C, TG, and total metabolic risk were observed in participants with high CRF (P < 0.05). Two-way ANCOVA provided significant interaction effects for five of the nine outcome variables (P < 0.05, 3.6%–4.8% of explained variance). Participants with high stress who also had high CRF levels had lower SBP, DBP, LDL-C, TG, and total cardiometabolic risk than participants with high stress but low or moderate CRF levels. No significant main or interaction effects occurred for BMI, total cholesterol, high-density lipoprotein cholesterol, and glycated hemoglobin.Better CRF is associated with more favorable levels of several cardiometabolic risk factors, specifically in participants experiencing high stress. Higher CRF may provide some protection against the health hazards of high chronic stress by attenuating the stress-related increase in cardiovascular risk factors.