The identification and cDNA cloning of bone-enriched osteonectin and parietal endoderm-enriched SPARC indicated that these proteins share greater than 90% homology. The present study reports substantial expression of this Mr 43,000 protein in human decidua and carcinoma. Metabolic labeling of human decidua tissue in organ culture demonstrated significant osteonectin biosynthesis. Further, Northern analysis and in situ hybridization showed that the osteonectin mRNA level in human decidua is very high. Immunohistochemically, the large mature decidual cells exhibited faint cytoplasmic immunoreactivity with antibodies to osteonectin and a distinct immunoreactivity of the newly deposited basement membranes encircling these cells. The intermediate-sized decidual cells exhibited a strong cytoplasmic immunostaining with antibodies to osteonectin. The small elongated stromal cells were devoid of osteonectin immunoreactivity. Blood vessels exhibited variable positive immunoreactivity. The osteonectin expression in 38 cases of human carcinomas was examined. In well-differentiated carcinomas osteonectin immunoreactivity was located in the basement membrane area, codistributing with laminin. Cytoplasmic osteonectin immunoreactivity was found in poorly differentiated carcinomas. Stromal cells in the peritumoral tissue and some vessels were immunoreactive. Using in situ hybridization, it appeared that both the tumor cells and the stromal cells contained osteonectin transcripts. In normal steady state human nonosseus tissues investigated, osteonectin was found inconsistently in the basement membranes only, as based on the present immunohistochemical technique. These results suggest that the osteonectin/SPARC gene appears activated in certain human tissues characterized by de novo formation of basement membrane.