Respiratory syncytial virus (RSV) is the most important microbiological cause of lower respiratory tract infection (LRTI) in infants. Mannan-binding lectin (MBL) is believed to play a major protective role in the vulnerable period in infancy where the maternal antibodies have been catabolized, and the adaptive immune system has not yet matured. Mutations in the promoter region and in exon 1 of the gene-encoding MBL result in low serum levels of MBL. MBL deficiency is the most common immunodeficiency on the African Continent with frequencies of the variant alleles up to 0.29. We investigated whether MBL deficiency has an impact on the hospitalization for LRTI caused by RSV in infants from Soweto, South Africa. The cases were ethnic black Africans identified through surveillance for RSV-LRTI at Chris Hani Baragwanath Hospital, Soweto, and the controls were sampled from four immunization clinics in the area. Fifty-five cases and 113 age- and sex-matched controls were identified. Seventy-six per cent were under 6 months of age, and 42% (n = 23) were under 3 months of age. No association was found between low levels of MBL or carriage of variant alleles and LRTI caused by RSV, odds ratio (OR) 1.00 (CI 0.99-1.03) and OR 1.24 (0.73-2.12). We did not find support for the hypothesis that MBL deficiency leads to the hospitalization for LRTI caused by RSV.