Background <p>While previous literature suggests that multimorbidity is linked to a higher risk of mortality, evidence is scarce among individuals in middle adulthood. We aimed to examine the association between physical multimorbidity and all-cause mortality among individuals aged 40–64 years at baseline in Japan.</p> Methods <p>Data were obtained from two cohort studies, the Japan Public Health Center-based Prospective Study (JPHC) and the Japan Epidemiology Collaboration on Occupational Health Study (J-ECOH). The study participants were 144,774 individuals aged 40–64 years at baseline who were followed up for a maximum of 29 and 10 years in the JPHC and J-ECOH, respectively. Multimorbidity was defined as the presence of ≥ 2 of 10 morbidities or conditions based on self-reported information. A Cox proportional hazards model was used to examine the association in relation to all-cause mortality. We calculated pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) using a random-effects meta-analysis model. Cause-specific analysis was performed using the JPHC dataset, which provided a sufficient number of events for mortality due to physical disorders, mental disorders/suicide, and unintentional injuries.</p> Results <p>During a follow-up of 2,304,375 person-years in the JPHC and 311,637 person-years in the J-ECOH, 23,611 and 275 deaths were recorded, respectively. Participants with vs. without physical multimorbidity at baseline were more likely to die prematurely in both cohorts with a pooled HR of 1.61 (95%CI = 1.29–2.01). Cause-specific analyses among the JPHC participants revealed that physical multimorbidity at baseline was linked with mortality due to physical disorders, mortality due to mental disorders/suicide, and mortality due to unintentional injuries.</p> Conclusions <p>Physical multimorbidity in middle adulthood is associated with an increased risk of all-cause mortality in Japan.</p>