The role of complement system in stem cell transplantation is largely unknown. In solid organ transplantation, endovascular C4d deposition, a degradation product of the classic complement pathway, is essential for early rejection diagnosis. We retrospectively analyzed all patients diagnosed with graft versus host disease (GVHD) for C4d deposition at Oklahoma University between years 2000 and 2008. A modified Banff07 grading system was used to quantify C4d deposition. 58 biopsies (40 skin, 18 colon) performed on patients clinically suspected of having GVHD and 12 controls (all colon biopsies) were analyzed for C4d deposition. We recorded “response to steroids” in all clinical GVHD cases and looked at whether C4d can be utilized as a predictor of steroid treatment response. Of 40 clinical skin GVHD cases, 27 showed positive C4d staining which did not correlate well with steroid sensitivity: 74% of positive C4d cases responded to steroid therapy compared to 92% for negative cases (p=0.2634). 94% of colon GVHD cases showed positive C4d staining compared to 17% in controls (p<0.001). Only 44% of clinical colon GVHD cases were confirmed pathologically by H&E, compared to 93% of skin GVHD cases. For colon GVHD cases, 61% had clinical grade III/IV, and 78% responded to steroids. Interestingly, 90% of negative H&E colon cases responded to steroids. In conclusion, C4d deposition is a valuable marker for detection of colon GVHD, indicating a potential role of complement system in the pathogenesis of GVHD. C4d staining is potentially an objective tool than can help pathologist, in addition to H&E, to diagnosed colon GVHD.