OBJECTIVE: The purpose of this review was to assess the joint relationship of cardiorespiratory fitness (CRF) and Body Mass Index (BMI) on both cardiovascular disease (CVD) and all-cause mortality risk. DESIGN: A systematic review and meta-analysis was conducted. Pooled HR and 95% CI were calculated using a three-level restricted maximum likelihood estimation random-effects model with robust variance estimation. The reference group was normal weight-fit and was compared with normal weight-unfit, overweight-unfit and fit, and obese-unfit and fit. DATA SOURCES: Electronic databases (PubMed/MEDLINE, Web of Science and SportDiscus) were searched following registration on PROSPERO. ELIGIBILITY CRITERIA: Articles meeting the following criteria were included: (1) published between January 1980 and February 2023, (2) prospective cohort study, (3) CRF assessed using a maximal or VO RESULTS: 20 articles were included in the analysis resulting in a total of 398 716 observations. Compared with the reference group, overweight-fit (CVD HR (95% CI): 1.50 (0.82-2.76), all-cause HR: 0.96 (0.61-1.50)) and obese-fit (CVD: 1.62 (0.87-3.01), all-cause: 1.11 (0.88-1.40)) did not have a statistically different risk of mortality. Normal weight-unfit (CVD: 2.04 (1.32-3.14), all-cause: 1.92 (1.43-2.57)), overweight-unfit (CVD: 2.58 (1.48-4.52), all-cause: 1.82 (1.47-2.24)) and obese-unfit (CVD: 3.35 (1.17-9.61), all-cause: 2.04 (1.54-2.71)) demonstrated 2-3-fold greater mortality risks. CONCLUSIONS: CRF is a strong predictor of CVD and all-cause mortality and attenuates risks associated with overweight and obesity. These data have implications for public health and risk mitigation strategies.