Cultured cells of various origins have been shown to be surrounded by a hyaluronan-containing coat, a structure that can be visualized by its ability to exclude large particles such as erythrocytes. When cultured in medium with no Or low concentrations of serum, the cells lose their coats, although they still produce hyaluronan; upon the addition of serum, the coats are formed again. Here, we show that the serum protein inter-alpha-inhibitor can replace whole serum as an inducer of the formation of the coats on fibroblasts and mesothelial cells. The physiological role of inter alpha-inhibitor has so far been unclear; our findings, together with those obtained with cumulus cell-oocyte complexes (Chen, L., Mao, S. J., and Larsen, W. J. (1992) J. Biol. Chen. 267, 12380-12386), suggest that inter-alpha inhibitor and related proteins have a general function as stabilizers of hyaluronan-containing pericellular coats.