Activation of the innate immune response in diseases such as rheumatoid arthritis and atherosclerosis leads to the production of proinflammatory cytokines that can promote collagenolysis. While a number of studies suggest that inflammation plays a major role in initiating collagen degradation, the effect of collagen and collagen-degradation fragments on the inflammatory response is not well understood. We now demonstrate that different collagen fragments can either augment or suppress IL-1beta production from human peripheral-blood monocytes. These data have wide-ranging implications for how amino acid variation in collagen affects disease and suggest that collagen degradation leads to the production of peptides that can modulate inflammation.