Context: Hospital-based studies have found that increased susceptibility to certain infections is associated with low serum levels of mannose-binding lectin (MBL) due to MBL variant alleles. However, the contribution of MBL insufficiency to incidence of common childhood infections at a population level is unknown. Objective: To investigate the effect of MBL insufficiency on risk for acute respiratory tract infection (ARI) in unselected children younger than 2 years. Design and Setting: Population-based, prospective, cohort study conducted in Sisimiut, Greenland. Participants: Two hundred fifty-two children younger than 2 years who were followed up weekly between August 1996 and August 1998 for morbidity surveillance. Main Outcome Measure: Risk of ARI, based on medical history and clinical examination, compared by MBL genotype, determined from blood samples based on presence of structural and promoter alleles. Results: A 2.08-fold (95% confidence interval [CI], 1.41 -3.06) increased relative risk (RR) of ARI was found in MBL-insufficient children (n=13) compared with MBL-sufficient children (n=239; P<.001). The risk association was largely restricted to children aged 6 to 17 months (RR, 2.92; 95% CI, 1.78-4.79) while less effect (RR, 1.47; 95% CI, 0.45-4.82) and no effect (RR, 1.00; 95% CI, 0.42-2.37) was shown among children aged 0 to 5 months and 18 to 23 months, respectively. Conclusion: These data suggest that genetic factors such as MBL insufficiency play an important role in host defense, particularly during the vulnerable period of childhood from age 6 through 17 months, when the adaptive immune system is immature.