Decorin belongs to a family of secreted, small, leucine-rich proteoglycans that affect matrix assembly and cellular growth. Ectopic expression of decorin proteoglycan or protein core as a mutated form lacking any glycosaminoglycan side chains induced growth suppression in neoplastic cells of various histogenetic origins, including tumor cells derived from gastrointestinal, genital, skeletal, cutaneous, or bone marrow tissues. Exogenously added recombinant decorin also suppressed overall growth of the parental cell lines. In all stably-transfected clones, growth retardation was specifically associated with induction of the potent cyclin-dependent kinase inhibitor p21, but not p27, and subsequent translocation of p21 protein into the nuclei of decorin-expressing cells. This led to a greater proportion of the cells arrested in G1 phase of the cell cycle. These changes were independent of functional p53 or retinoblastoma protein. De novo expression of decorin in HCT116 human colon carcinoma cells harboring a disrupted p21 gene failed to induce growth suppression, in contrast to the wild-type cells in which p21 and growth arrest could be induced. These findings indicate that ectopic production of decorin protein core can retard the growth of a variety of tumor cells and that endogenous p21 is a required downstream effector of this biological axis.