Mice of the C5-deficient DBA/2J and B10.D2/oSnJ inbred strains were aerosolized with Staphylococcus aureus, and the pulmonary clearance of bacteria was determined 4 h later. Both C5-deficient strains had a significantly decreased lung clearance of S. aureus compared with their genetically closest C5-sufficient relatives, DBA/1J and B10.D2/nSnJ strains, respectively. Serum hemolytic activity and pulmonary clearance of S. aureus were also investigated in F1 and F2 progenies (DBA/1J X DBA/2J and DBA/2J X B10.D2/oSnJ). Serum hemolytic activity was present in all F1 (DBA/1J X DBA/2J) mice, and their pulmonary clearance of S. aureus was no different from that of the C5-sufficient parents (DBA/1J). The absence of serum hemolytic activity (absence of C5) in all mice from F1 and F2 (DBA/2J X B10.D2/oSnJ) and 20% of the F2 (DBA/1J X DBA/2J) was related to a decreased lung clearance of S. aureus. These results are consistent with an autosomal recessive pattern of heredity for the murine abnormality in pulmonary clearance of S. aureus.