Objectives: We hypothesise that rising prevalence rates of non-communicable diseases (NCDs) increase infection risk and worsen outcomes among socially disadvantaged Indigenous Australians undergoing a rapid epidemiological transition. Design: Available pathology, imaging and discharge morbidity codes were retrospectively reviewed for a period of 5 years prior to admission with a bloodstream infection (BSI), 1 January 2003 to 30 June 2007. Participants: 558 Indigenous and 55 non-Indigenous community residents of central Australia. Outcome measures: The effects of NCDs on risk of infection and death were determined after stratifying by ethnicity. Results: The mean annual BSI incidence rates were far higher among Indigenous residents (Indigenous, 937/100 000; non-Indigenous, 64/100 000 personyears; IRR=14.6; 95% CI 14.61 to 14.65, p<0.001). Indigenous patients were also more likely to have previous bacterial infections (68.7% vs 34.6%; respectively, p<0.001), diabetes (44.3% vs 20%; p<0.001), harmful alcohol consumption (37% vs 12.7%; p<0.001) and other communicable diseases (human T-lymphotropic virus type 1, 45.2%; strongyloidiasis, 36.1%; hepatitis B virus, 12.9%). Among Indigenous patients, diabetes increased the odds of current Staphylococcus aureus BSI (OR=1.6, 95% CI 1.0 to 2.5) and prior skin infections (adjusted OR=2.1, 95% CI 1.4 to 3.3). Harmful alcohol consumption increased the odds of current Streptococcus pneumoniae BSI (OR=1.57, 95% CI 1.02 to 2.40) and of previous BSI (OR=1.7, 95% CI 1.1 to 2.5), skin infection (OR=1.7, 95% CI 1.1 to 2.6) or pneumonia (OR=4.3, 95% CI 2.8 to 6.7). Twenty-six per cent of Indigenous patients died at a mean (SD) age of 47±15 years. Complications of diabetes and harmful alcohol consumption predicted 28-day mortality (non-rheumatic heart disease, HR=2.9; 95% CI 1.4 to 6.2; chronic renal failure, HR=2.6, 95%CI 1.0 to 6.5; chronic liver disease, HR=3.3, 95% CI 1.6 to 6.7). Conclusions: In a socially disadvantaged population undergoing a rapid epidemiological transition, NCDs are associated with an increased risk of infection and BSI-related mortality. Complex interactions between communicable diseases and NCDs demand an integrated approach to management, which must include the empowerment of affected populations to promote behavioural change.