The ability of collagen and collagen-derived peptides to act as chemotactic stimuli was investigated by in vitro chemotaxis assays. Native human and chick skin collagen (type I) and alpha-chains obtained from purified chick skin collagen were each chemotactic for human peripheral blood monocytes. In addition, smaller peptides obtained either by digesting native collagen with bacterial collagenase or by degrading purified alpha-chains with cyanogen bromide or pepsin were also chemotactic for monocytes. In contrast, native collagen, alpha-chains, and smaller collagen-derived peptides were not chemotactic for human neutrophils. Since collagen is degraded at sites of tissue damage and inflammation, our findings suggest the possibility that such collagen-derived degradation products might directly serve as chemotactic stimuli for human peripheral blood monocytes in vivo.