Homelessness is associated with increased risks of mortality but it has not previously been possible to distinguish whether this is typical of other socio-economically deprived populations, the result of a higher prevalence of morbidity or an independent risk of homelessness itself. The aim of this study was to describe mortality among a cohort of homeless adults and adjust for the effects of morbidity and socio-economic deprivation. Retrospective 5-year study of two fixed cohorts, homeless adults and an age- and sex-matched random sample of the local non-homeless population in Greater Glasgow National Health Service Board area for comparison. Over 5 years of observation, 1.7% (209/12 451) of the general population and 7.2% (457/6323) of the homeless cohort died. The hazard ratio of all-cause mortality in homeless compared with non-homeless cohorts was 4.4 (95% CI: 3.8-5.2). After adjustment for age, sex and previous hospitalization, homelessness was associated with an all-cause mortality hazard ratio of 1.6 (95% CI: 1.3-1.9). Homelessness had differential effects on cause-specific mortality. Among patients who had been hospitalized for drug-related conditions, the homeless cohort experienced a 7-fold increase in risk of death from drugs compared with the general population. Homelessness is an independent risk factor for deaths from specific causes. Preventive programmes might be most effectively targeted at the homeless with these conditions.