To evaluate the benefit and risk of low-dose acetylsalicylic acid (aspirin) in patients from remote Aboriginal communities in the Northern Territory, Australia. Design Retrospective cohort study using primary care and hospital data routinely used for healthcare. Aspirin users and non-users were compared before and after controlling confounders by matching. Marginal structural models (MSM) were applied to ascertain the benefit and risk. Setting The benefit and harm of aspirin were investigated in patients aged ≥18 years from 54 remote Aboriginal communities. Participants None had a previous cardiovascular event or major bleeds. Patients on anticoagulants or other antiplatelets were excluded. Intervention Aspirin at a dose of 75-162 mg/day. Outcome measures Endpoints were all-cause, cardiovascular mortality and incidences of cardiovascular events and major bleeds. Results 8167 predominantly Aboriginal adults were included and followed between July 2009 and June 2017 (aspirin users n=1865, non-users n=6302, mean follow-up 4 years with hospitalisations 6.4 per person). Univariate analysis found material differences in demographics, prevalence of chronic diseases and outcome measures between aspirin users and non-users before matching. After matching, aspirin was significantly associated with reduced all-cause mortality (HR=0.45: 95% CI 0.34 to 0.60; p<0.001), but not bleeding (HR=1.13: 95% CI 0.39 to 3.26; p=0.820). After using MSMs to eliminate the effects of confounders, loss of follow-up and time dependency of treatment, aspirin was associated with reduced all-cause mortality (HR=0.60: 95% CI 0.47 to 0.76; p<0.001), independent of age (HR=1.06; p<0.001), presence of diabetes (HR=1.42; p<0.001), hypertension (HR=1.61; p<0.001) and alcohol abuse (HR=1.81; p<0.001). No association between aspirin and major bleeding was found (HR=1.14: 95% CI 0.48 to 2.73; p=0.765). Sensitivity analysis suggested these findings were unlikely to have been the result of unmeasured confounding. Conclusion Aspirin was associated with reduced all-cause mortality. Bleeding risk was less compared with survival benefits. Aspirin should be considered for primary prevention in Aboriginal people with high cardiovascular risk.