Objective. We examined serum anti-p53 antibodies (S-p53Ab) in colorectal cancer. Specifically, we retrospectively investigated the use of S-p53Ab as a prognostic marker after surgery for colorectal cancer. Materials and Methods. The levels of S-p53Ab, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were measured in 160 colorectal cancer patients who underwent surgical treatment. The rate of postoperative change (RPC) in the S-p53Ab titer was calculated as [subsequent antibody titer-lowest titer]/lowest titer. Results. A relationship between recurrence and RPC in the S-p53Ab titer was not observed in patients who tested negative for S-p53Ab preoperatively. In addition, no patients, who tested negative for S-p53Ab preoperatively, tested positive for S-p53Ab at the follow-up after surgery. Of the patients who tested positive for S-p53Ab preoperatively, those recurrences had a significantly higher RPC compared with those who did not (p<0.001). Conclusions. Although S-p53Ab is not a significant tumor marker in patients who test negative preoperatively, increases in the S-p53Ab titer should be continuously monitored and measured in patients who are positive for this antibody preoperatively, regardless of whether they later test negative.