Background: Severe anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology is lacking and needed to improve outcomes. Methods: HIV-infected adults with severe (haemoglobin ≤70g/l) or very severe anaemia (haemoglobin ≤50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes of severe anaemia of anaemia and associations with anaemia severity and mortality were explored. Results: 199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. Over two potential causes for anaemia were present in 94% of the patients; including iron deficiency (55.3%), underweight (BMI<20: 49.7%), TB-infection (41.2%) and unsuppressed HIV-infection (viral load >1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 16 days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2). Conclusion: Mortality among severely anaemic HIV-infected adults is strikingly high. Clinicians must be aware of the urgent need for a multifactorial approach, including starting or optimising HIV treatment; considering TB treatment, nutritional support and attention to potential renal impairment.