Context Previous studies have implicated a deficiency in the inflammatory response in women who develop endometriosis. The specific immunological deficits have not been completely elucidated. Objective Our objective was to identify differences in protein expression in serum that might shed light on the pathophysiology of endometriosis. Design and Setting This cross-sectional study of women undergoing laparoscopy between 2003 and 2005 took place at a university medical center. Patients Patients included consenting women age 18-49 yr undergoing surgery for pain and/or infertility or elective tubal ligation. Women with acute or chronic medical conditions were excluded. Intervention Blood was collected preoperatively. Main Outcome Measure Proteomic analysis of serum was done using two-dimensional difference gel electrophoresis. Results We found 25 protein spots with a significant difference in abundance between women with endometriosis and controls, including acute-phase proteins and complement components. The abundance of vitamin D-binding protein was higher in all endometriosis pools by a factor of approximately 3 compared with the control pool (P < 0.02). Analysis of specific allele products using nano-LC-ESI-MS indicated that it was the GC*2 allele product that was in greater concentration in serum pools, as well as in single validation samples, in women with endometriosis (P = 0.006). In contrast to the GC*1 allele product, which is readily converted to a potent macrophage factor (Gc protein-derived macrophage-activating factor), the GC*2 allele product undergoes practically no such conversion. Conclusions We speculate that the inability to sufficiently activate macrophages’ phagocytotic function in those carrying the GC*2 polymorphism (more prevalent in endometriosis) may allow endometriotic tissues to implant in the peritoneal cavity. Future studies evaluating specific vitamin D-binding protein polymorphisms as a risk factor for endometriosis in larger populations of women are warranted.