Hypertrophic scar after burn injury is a significant problem. Previous studies have examined the roles for decorin, interleukin-1β, and transforming growth factor-β1 in hypertrophic scar formation locally, but few have considered their systemic influence. The authors conducted a pilot study to examine whether serum levels of these molecules could predict hypertrophic scar formation. Serum levels were measured using enzyme-linked immunosorbent assay, and hypertrophic scar formation determined from chart reviews. Peripheral blood mononuclear cells and fibroblasts were stimulated with decorin, interleukin-1β, and transforming growth factor-β1, and expression of profibrotic molecules examined using flow cytometry, immunofluorescence microscopy, quantitative polymerase chain reaction, and mass spectrometry. Multiple linear regression analysis suggested early serum levels of decorin and interleukin-1β, and late serum levels of transforming growth factor-β1 were predictive of hypertrophic scar formation. Decorin up-regulated the expression of toll-like receptor 4 and C-X-C receptor 4 in peripheral blood mononuclear cells, and interleukin-1β up-regulated fibroblast production of C-X-C ligand 12. Transforming growth factor-β1 up-regulated, and interleukin-1β down-regulated, the production of profibrotic cytokines, collagen, and myofibroblast differentiation. The model predicting hypertrophic scar formation is supported by clinical results and limited in vitro experiments.