To date, there is no study addressing the time-varying confounding bias in the association of handgrip strength (HGS) with all-cause or cardiovascular mortality. Therefore, we conducted marginal structural models (MSM) to provide causal estimations on the associations of HGS with all-cause and cardiovascular mortality in a representative sample of adults aged 50 years or older. Data from 29 countries including 121,116 participants (276,994 observations; mean age 63.7 years; 56.3 % women) free from prior heart attack or stroke were retrieved from consecutive waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). During a median of 7.7 years follow-up (interquartile range 3.8-11.8) and 1,009,862 person-years, 6407 participants (5.3 %) died due to all causes, and 2263 (1.9 %) died due to cardiovascular diseases. Using repeated measures of handheld dynamometry, we determined absolute and relative to body mass index HGS of each participant. We applied adjusted MSM to estimate hazard ratios (HRs) associated with changes over time in HGS addressing the time-varying confounding bias. An increase of 5 kg in HGS was associated with a reduced risk of all-cause [HR 0.86, 95 % confidence interval (CI), 0.86-0.90], overall cardiovascular (HR 0.86, 95 % CI 0.82-0.86), heart attack (HR 0.90, 95 % CI 0.86-0.95), and stroke (HR 0.86, 95 % CI 0.82-0.90) mortality. The associations of relative HGS were of stronger magnitude in all cases. Our findings provide critical evidence on the importance of increasing general muscle strength in older adults to reduce mortality risk, particularly concerning cardiovascular causes.