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To examine the relationship between maternal HIV infection, placental malaria infection, and infant mortality as a first step in investigating the possibility of increased vertical transmission of HIV due to placental malaria infection.Retrospective analysis of data from a cohort study of mothers and infants in rural Malawi conducted from 1987 to 1990.Pregnant women in Malawi were enrolled in a study examining chemoprophylaxis during pregnancy. At delivery, placental malaria infection status was determined. Infants born into this study were visited every 2 months for the first 2–3 years of life. Deaths were investigated using a standardized Verbal autopsy' interview. Maternal serum collected during pregnancy was tested for antibodies to HIV-1 by enzyme-linked immunosorbent assay with Western blot confirmation.Overall, 138 (5.3%) of 2608 women in the study were HIV-1-seropositive. Infant mortality rates were 144 and 235 per 1000 live births for children born to HIV-seronegative and HIV-seropositive women, respectively (P<0.001). In a multivariate model, the odds of dying during the post-neonatal period for an infant born to a mother with both placental malaria and HIV infection was 4.5 times greater than an infant born to a mother with only placental malaria, and between 2.7 and 7.7 times greater (depending on birthweight) than an infant born to a mother with only HIV infection.This study strongly suggests that exposure to both placental malaria infection and maternal HIV infection increases post-neonatal mortality beyond the independent risk associated with exposure to either maternal HIV or placental malaria infection., If confirmed, malaria chemoprophylaxis during pregnancy could decrease the impact of transmission of HIV from mother to infant.