Abstract Aim: Our aim was to assess the associations between cardiorespiratory fitness (CRF) and body mass index (BMI) in youth and five-year mortality following the diagnosis of 18 site-specific cancers in men. Methods: We collected data on all men who underwent military conscription at ages 16-25 from 1968 through 2005 in Sweden. CRF was assessed as maximal aerobic workload on a cycle ergometer test and was classified as low, moderate, or high. BMI (kg/m2) was classified as underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9), or obesity (>30). Data was cross-linked on individual level through the Swedish unique identification number with follow-up data from national registers with high validity containing information on cancer diagnosis and mortality. Follow-up started at diagnosis and continued until death, emigration, five years after diagnosis, or end of follow-up (2019-12-31), whichever happened earliest. Time-to-event multivariable Cox regression analyses included CRF and BMI as well as age, year, and site of conscription and age at diagnosis. For CRF, primary analyses tested linear trends with categorical comparisons for interpretation while categorical comparisons were primary analyses for BMI. Results: 84,621 cancer cases were included in the main analyses. The mean age at diagnosis of any cancer was 53 years and follow-up data were available during a mean of 6.5 years. Lower CRF and higher BMI were independently associated with higher mortality for several cancer sites (table 1). Conclusion: We report clinically relevant, dose-dependent associations between CRF and BMI in youth and 5-year mortality after diagnosis of 18 site-specific cancers in men. The associations with mortality may be due to both direct cancer inhibition and an improved tolerance to withstand cancer treatment. These results further strengthen the incentive for promoting a healthy lifestyle during the whole lifespan of the population. Table 1. Five-year mortality by cardiorespiratory fitness (CRF) and body mass index (BMI). Cardiorespiratory fitness (ref = low) BMI (ref = normal weight), *= p<0.05, **=p<0.01, ***=p<0.001 Cancer site n cases (% mortality) High p for linear trend for CRF Underweight Overweight Obesity HRR (95% CI) HRR (95% CI) HRR (95% CI) HRR (95% CI) Any cancer 84,621(16%) 0.70 (0.67-0.73) *** 0.98 (0.93-1.04) 1.38*** (1.30-1.46) 1.92*** (1.70-2.17) Malignant skin 28,359(4%) 0.80 (0.69-0.93) *** 0.96 (0.78-1.17) 1.53*** (1.26-1.86) 2.16*** (1.33-3.49) Bronchi and lung 2,502 (68%) 0.82 (0.72-0.94) *** 0.92 (0.80-1.07) 1.06 (0.87-1.28) 1.17 (0.81-1.69) Head & neck 3,549 (20%) 0.69 (0.57-0.84) *** 1.07 (0.84-1.37) 1.52** (1.19-1.94) 1.41 (0.75-2.64) Esophagus 991 (71%) 0.92 (0.76-1.13) 1.00 (0.76-1.32) 1.11 (0.88-1.39) 1.15 (0.75-1.76) Stomach 1,269 (62%) 0.94 (0.78-1.13) 0.95 (0.73-1.23) 1.06 (0.85-1.32) 1.20 (0.78-1.86) Pancreas 1,809 (71%) 0.83 (0.72-0.96) * 1.07 (0.89-1.30) 0.96 (0.80-1.15) 1.38 (0.89-2.16) Liver, bile ducts and gallbladder 1,573 (68%) 0.88 (0.74-1.03) * 1.11 (0.90-1.36) 1.00 (0.81-1.22) 1.14 (0.75-1.71) Colon 4,265 (31%) 0.96 (0.83-1.10) 1.13 (0.94-1.36) 0.99 (0.82-1.20) 1.12 (0.78-1.61) Rectum 3,123 (27%) 0.82 (0.68-0.98) ** 1.01 (0.79-1.28) 1.47** (1.17-1.85) 1.50 (0.93-2.44) Kidney 2,288 (24%) 1.07 (0.86-1.33) 0.70 (0.48-1.02) 1.36* (1.07-1.73) 1.83** (1.20-2.79) Bladder 3,078 (12%) 0.71 (0.55-0.93) * 0.75 (0.51-1.09) 0.93 (0.63-1.39) 2.06* (1.09-3.09) Prostate 19,686(5%) 0.83 (0.70-0.97) ** 0.83 (0.66-1.05) 1.30* (1.02-1.66) 2.43** (1.40-4.21) Central nervous system 2,937 (1,566) 0.89 (0.78-1.02) 1.05 (0.88-1.27 1.03 (0.85-1.23) 0.94 (0.58-1.52) Thyroid gland 848 (11%) 0.94 (0.55-1.62) 1.27 (0.60-2.69) 1.36 (0.69-2.68) 3.53** (1.41-8.83) Leukemia 2,698 (24%) 0.98 (0.80–1.20) 1.46** (1.12-1.89) 0.96 (0.73-1.28) 1.34 (0.77-2.33 Myeloma 1,209 (21%) 1.19 (0.86-1.65) 1.66* (1.06-2.58) 1.40 (0.93-2.09) 0.71 (1.18-2.88) Hodgkin's lymphoma 1,112 (10%) 0.82 (0.49-1.36) 1.55 (0.85-2.84) 0.89 (0.47-1.69) 2.47 (0.98-6.21) Non-Hodgkin's lymphoma 3,261 (16%) 0.77 (0.62-0.96) ** 0.81 (0.57-1.14) 1.14 (0.86-1.52) 1.26 (1.03-1.24) Citation Format: Aron Onerup, Kirsten Mehlig, Agnes af Geijerstam, Elin Ekblom-Bak, Hans-Georg Kuhn, Lauren Lissner, Mats Börjesson, Maria Åberg. Cardiorespiratory fitness and BMI in youth and five-year mortality after site-specific cancer in men: a population-based cohort study with register linkage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5770.