Keloid scarring is a form of fibroproliferative dermal wound healing characterized by growth beyond the confines of the original wound. Fibrocytes, derived from peripheral blood mononuclear cells and inhibited by serum amyloid P (SAP), have been linked to other fibroproliferative diseases. We hypothesized that peripheral blood mononuclear cells of keloid formers have a higher propensity to differentiate into fibrocytes and are more resistant to the effects of SAP. To test this hypothesis, plasma was isolated from peripheral blood samples of keloid (n = 10) and age/sex/race-matched control (n = 10) subjects, and SAP levels were measured by enzyme-linked immunosorbent assay. Equal numbers of peripheral blood mononuclear cells were also isolated from these samples and fibrocytes cultured in serum-free media with increasing concentrations of SAP. No difference in plasma SAP levels was found between keloid and control subjects. In the absence of SAP, keloid patients (n = 7) had almost 20 times more fibrocytes than controls (n = 7) in culture (median: 1,087 cells vs. 60 cells; p < 0.01). SAP inhibited the differentiation of keloid fibrocytes in vitro, although a higher concentration of SAP was needed when compared with controls (20 μg/mL keloid vs. 5 μg/mL control). Fibrocytes may contribute to the pathogenesis of keloids, and SAP has potential as a therapeutic agent in the prevention of these lesions.