House structure is associated with Plasmodium falciparum infection in a low-transmission setting in southern Zambia

House structure may influence the risk of malaria by affecting mosquito entry and indoor resting. Identification of construction features associated with protective benefits could inform vector control approaches, even in low-transmission settings. We examined the association between house structure and malaria prevalence in a cross-sectional analysis of 2,788 children and adults residing in 866 houses in a low-transmission area of Southern Province, Zambia, over the period 2008–2012. Houses were categorized according to wall (brick/cement block or mud/grass) and roof (metal or grass) material. Malaria was assessed by point-of-care rapid diagnostic test (RDT) for Plasmodium falciparum. We identified 52 RDT-positive individuals residing in 41 houses, indicating an overall prevalence in the sample of 1.9%, ranging from 1.4% to 8.8% among the different house types. Occupants of higher quality houses had reduced odds of P. falciparum malaria compared with those in the lowest quality houses after controlling for bed net use, indoor insecticide spraying, clustering by house, cohabitation with another RDT-positive individual, transmission season, ecologic risk defined as nearest distance to a Strahler-classified third-order stream, education, age, and gender (adjusted odds ratio [OR]: 0.26, 95% confidence interval [CI]: 0.09–0.73, P = 0.01 for houses with brick/cement block walls and metal roof; OR: 0.22, 95% CI: 0.09–0.52, P < 0.01 for houses with brick/cement block walls and grass roof). Housing improvements offer a promising approach to vector control in low-transmission settings that circumvents the threat posed by insecticide resistance, and may confer a protective benefit of similar magnitude to current vector control strategies.