Background <p>Observational studies examining the relation of body composition with lifespan are inconsistent. We conducted a Mendelian Randomization (MR) study to assess effects of key features of body composition on lifespan.</p> Methods <p>We conducted a MR study using inverse variance weighting to investigate the impact of measures of body composition on lifespan, and we also adjusted fat-free mass and appendicular lean mass for potential confounding by fat mass, and assessed mediation by waist circumference in men and women.</p> Results <p>In univariable MR, genetically predicted fat mass (per standard deviation higher) decreased men’s lifespan by 2.69 years (95% confidence interval [CI] –3.14 to –2.23) and women’s by 2.48 years (95% CI –3.04 to –1.93), with similar findings for body fat percentage and waist circumference. Appendicular lean mass and grip strength were positively associated with lifespan in men, but not women. In multivariable MR, fat-free mass was also beneficial for men. The effect of BMI on lifespan was largely mediated by waist circumference.</p> Conclusion <p>Our study provides additional evidence highlighting the role of body composition rather than relying solely on BMI, with possibly a greater role of lean or fat-free mass in men. Waist circumference is a key target of intervention for men and women.</p>