Mice homozygous for the motheaten (me) and viable motheaten (me) mutations develop a progressively severe inflammatory disease in association with profound disruption of normal hematopoiesis. These mutant mice have been previously shown to manifest abnormally high expression in the bone marrow of cDNAs encoding three members of the stefin family of cysteine proteinase inhibitors. The data reported here reveal that increases in levels of both stefin transcripts and proteins occur in bone marrow, splenic and pulmonary tissues of me and mev mice, and correlate with the abnormal expansion of stefin A-producing myelomonocytic cells in these tissues. Increases in stefin expression are also apparent in me and mev skin and appear to reflect focal hyperplasia of stefin-producing epidermal cells as well as infiltration by stefin-expressing monocytic and granulocytic cells. Because the increases in stefin protein levels occur in the same tissues that are most adversely affected by the me mutation, it appears that overexpression of these proteins may distinguish the cell population responsible for disease pathogenesis and may be relevant to the severe tissue inflammation and damage observed in these mutant mice.