Surfactant proteins A (SP-A), B (SP-B), and C (SP-C) are important surface active molecules that interact with phospholipid in the lung to form pulmonary surfactant. Pulmonary surfactant is synthesized by the respiratory epithelium in late gestation and secreted into the alveolar lumen, where it functions to reduce surface tension during respiration after birth. Although surfactant deficiency is the principal cause of respiratory distress syndrome (RDS) in premature infants, RDS in the full-term infant may also be associated with abnormalities in surfactant protein expression. In order to test this hypothesis, biopsy or autopsy material from full- or near-term infants with RDS was obtained as part of an ongoing program to screen these infants for hereditary SP-B deficiency, a fatal lung disease in full-term infants. Surfactant protein expression was evaluated by immunohistochemistry using antisera to SP-A, SP-B, proSP-B, and proSP-C. Confirmed hereditary SP-B deficiency (n=13) was characterized by the absence of cellular staining for SP-B and by the accumulation of SP-A and proSP-C positive alveolar proteinosis material. No hyaline membrane formation was observed. In contrast, a group of infants with unexplained respiratory failure (n=15) was identified in which immunostaining for proSP-C was absent or undetectable without the use of antigen retrieval. The histopathology of these infants was characterized by congestion, edema, alveolar collapse and the formation of hyaline membranes, which were immunopositive for SP-A, SP-B and proSP-B. In 4 cases, more than one child born to the same parents was affected and, in one of these families, the parents were first cousins, suggesting a genetic basis for disease. DNA was available from one affected child and from both parents in 3 other families. Sequence analysis, however, did not reveal any deviations from the published sequences in the coding regions of the SP-C gene. We conclude that reduced expression of SP-C is associated with fatal lung disease in full- or near-term infants. Although this could be secondary to lung injury of unknown etiology, we speculate that mutations in either regulatory regions of the SP-C gene or in other genes needed for proper SP-C expression may account for some of these cases.