Spontaneous pulmonary alveolar proteinosis (PAP), which resembles human PAP, was found in aging (35 to 40 weeks) germ-free SCID-beige (scid/scid-bg/bg) mice. Spontaneous PAP was not observed in germ-free SCID mice. We describe the induction of PAP in SCID mice monoassociated with a pure culture of Candida albicans for 15 to 40 weeks. The gastrointestinal tracts only are colonized, and disseminated or pulmonary candidiasis does not occur. Another spontaneous form of PAP, designated type II, was discovered in germ-free beige (bg/bg and bg/+) mice and in beige-nude (bg/bg-nu/nu) mice. In this form of PAP, macrophages appear to be unable to digest the ingested phospholipoprotein complex and then accumulate in the alveolar spaces. These murine models should prove useful in elucidating the relationships between immune deficiencies, infections, and cytokine regulation of granulocyte and macrophage production and function in pulmonary alveolar proteinosis.