We conducted a 1-year longitudinal prospective study of infants born in a traditional rural indigenous community of Guatemala. Three hundred twenty-nine infants surviving birth and the first day of life were followed during the first 3 months of life. Surveillance included routine household and well baby clinic visits and clinic visits for minor illnesses. Detection of potentially lethal illnesses depended on orientation of families and midwives to important symptoms and to the need for immediate medical evaluation if such symptoms were identified. We identified 38 episodes of lethal and potentially lethal illness. Thirty-five (92%) of these episodes were infectious diseases, principally sepsis during the neonatal period and acute lower respiratory infection in Months 2 and 3. Of all study infants, low birth weight (less than 2500 g) infants comprised 14% and premature (less than 37 weeks gestation) infants comprised 1%. Premature infants had a relative risk of lethal and potentially lethal illnesses of 11.1 (95% confidence interval, 3.6 to 34.4) compared with normal term infants, and no premature infant survived the first 3 months of life despite medical intervention. Low birth weight infants had a relative risk of 3.2 (95% confidence interval, 1.5 to 6.6), but with medical intervention all but 2 survived. Despite their lower risk, because of their much greater number normal term infants experienced 60% of lethal and potentially lethal illnesses. Among all study infants medical intervention was associated with survival of 86% of lethal and potentially lethal infectious illnesses and with a rate of neonatal mortality among study children significantly lower than rates documented in previous years in the same community.