It has been suggested that serum-mediated endothelial cell injury in scleroderma might contribute to disease pathogenesis. We compared the effect of serum from 28 scleroderma patients on human umbilical cord vein endothelial cell and human foreskin fibroblast proliferation with sera from 28 healthy controls, 13 patients with isolated Raynaud's disease, 22 patients with systemic lupus erythematosus, 19 patients with rheumatoid arthritis, and 15 patients with other connective tissue diseases. Five sera (2 scleroderma, 1 morphea, 12 rheumatoid arthritis, 1 systemic lupus erythematosus) markedly suppressed 3H-thymidine incorporation into both endothelial cells and fibroblasts (to greater than 3 SD below the mean of the control group). These sera were also cytotoxic to endothelial cells and fibroblasts in a 51Cr release assay. Three additional sera (1 Raynaud's, 2 controls) suppressed endothelial cell proliferation moderately (greater than 2 SD but less than 3 SD from control mean) but did not affect fibroblasts. Mean 3H-thymidine incorporation by endothelial cells and fibroblasts in scleroderma serum was comparable to that of the other disease and control groups. In contrast to previous studies, we found serum-mediated endothelial cell cytotoxicity occurred infrequently in scleroderma, occurred also in other connective tissue diseases, and was without target cell specificity. Furthermore, scleroderma serum did not appear to stimulate fibroblast proliferation.