Background: Comorbid disease may increase mortality in persons with schizophrenia, but how specific diseases are associated with natural and unnatural death in different age groups is unclear. Aims: To investigate the association between eight major comorbid diseases and death from natural and unnatural causes in different age groups in persons with schizophrenia. Method: Retrospective register-based cohort study in 77,794 persons with schizophrenia in Denmark, 1977–2015. Using Cox regression in matched cohorts, we estimated hazard ratios for natural and unnatural death in three age groups (<55 years, 55–64 years, ≥65 years). Results: Hypertensive disease, atrial fibrillation, coronary heart disease, cerebrovascular disease, heart failure, type 2 diabetes, liver disease and chronic kidney disease were all strongly associated with natural death, with the strongest associations observed in persons <55 years (hazard ratio [HR] range 1.98–7.19). The strongest associations were observed for heart failure (HR 7.19, 95 % confidence interval [CI] 5.57–9.28; HR 4.56, CI 3.85–5.40; HR 2.83, CI 2.53–3.17), liver disease (HR 4.66, CI 3.59–6.05; HR 4.70, CI 3.55–6.22; HR 2.57, CI 1.98–3.34) and chronic kidney disease (HR 6.59, CI 1.66–26.1; HR 7.37, CI 3.03–17.9; HR 2.86, CI 1.84–4.46) for persons <55 years, 55–64 years and ≥65 years, respectively. Liver disease was strongly associated with unnatural death in persons <55 years (HR 5.42, CI 3.01–9.75); associations with the remaining comorbidities were weaker. Conclusions: Comorbid disease was strongly associated with natural death, with the strength of the associations decreasing with age. Comorbid disease was also modestly associated with unnatural death, regardless of age.