BACKGROUND: The global burden of anemia is large especially in sub-Saharan Africa, where HIV is common and lifestyles are changing rapidly with urbanization. The effects of these changes are unknown. Studies of anemia usually focus on pregnant women or children, among whom the burden is greatest. We describe prevalence and risk factors for anemia among rural and urban men and women of all ages in Malawi. METHODS: We analyzed data from a population-wide cross-sectional survey of adults conducted in two sites, Karonga (rural) and Lilongwe (urban), commencing in May 2013. We used multinomial logistic regression models, stratified by sex to identify risk factors for mild and moderate-to-severe anemia. RESULTS: Anemia prevalence was assessed among 8,926 men (age range 18-100 years) and 14,978 women (age range: 18-103 years). Weighted prevalence levels for all, mild, and moderate-to-severe anemia were 8.2, 6.7 and 1.2% in rural men; 19.4, 12.0 and 7.4% in rural women; 5.9, 5.1 and 0.8% in urban men; and 23.4, 13.6 and 10.1% in urban women. Among women, the odds of anemia were higher among urban residents and those with higher socioeconomic status. Increasing age was associated with higher anemia prevalence in men. Among both men and women, HIV infection was a consistent risk factor for severity of anemia, though its relative effect was stronger on moderate-to-severe anemia. CONCLUSIONS: The drivers of anemia in this population are complex, include both socioeconomic and biological factors and are affecting men and women differently. The associations with urban lifestyle and HIV indicate opportunities for targeted intervention.