BACKGROUND AND AIMS: Skeletal muscles make up about 40% of the body mass, but the effects of skeletal muscle mass (SMM) on blood pressure (BP) and the heart remain unclear and were explored in this study. METHODS: The study used cross-sectional and longitudinal cohort designs with data from 492 498 UK Biobank (ID 54078) participants without a history of stroke [mean (SD) age 56.5 (8.1) years, 45% men, 94% white]. Muscle mass index (MMI) was measured by bioimpedance analysis, lean mass index by DEXA, and thigh MMI by MRI, fat mass index (FMI) by bioimpedance and DEXA, left ventricular mass index (LVMI) by MRI. Multivariable regression was used to relate muscle mass, BP, and LVMI. RESULTS: On cross-sectional analysis, people with hypertension have higher values of all muscle mass metrics, which were independently associated with higher SBP and DBP after adjustment for age, sex, use of BP-lowering drugs and their interactions. Each 1 kg/m2 higher muscle mass was associated with higher SBP by 0.67 [95% confidence interval (CI) 0.63-0.71] mmHg for MMI, 0.82 (95% CI 0.68-0.97) mmHg for lean mass index and 4.7 (95% CI 4.3-5.1) mmHg for thigh MMI. On longitudinal cohort analyses, higher values of muscle mass changes were independently associated with higher SBP and DBP after adjustment for age, sex and FMI (for SBP per 1 kg/m2 increase) MMI during first follow-up of 4.3 years was independently associated with 2.2 (95% CI 1.9-2.5) mmHg increase in SBP, with consistent findings during longer follow-ups and MMI assessment by DEXA and MRI (P < 0.001 for all). Similarly, higher values of muscle mass metrics and their follow-up changes were independently associated with higher LVMI on cross-sectional and cohort analysis. CONCLUSION: Higher SMM is associated with higher BP and LVMI, independently of adiposity. Further research is needed to establish whether the observed association is causal and to identify the optimal exercise modes for optimal BP and better health outcomes.