Because of the important role in inflammation and tissue regeneration, toll-like receptors (TLR) are likely candidates to mediate effects of the innate immune system on tumorigenesis. The aim of this study was to investigate the expression and clinical relevance of TLR in colorectal cancer (CRC). The expressions of TLR3, TLR4, TLR7, and TLR9 were analyzed in 104 patients with resectable CRC by immunohistochemistry. The evaluation of the expression consisted on measuring the overall level of TLR expression and by each cell type. The results showed a direct association between the histologic grade of tumor and TLR9 expression by tumor cells. TLR4 expression by tumor cells was significantly associated with a lower rate of tumor recurrence, whereas the expression by fibroblasts was significant and independently associated with a high rate of tumor recurrence and with a shortened overall survival in patients; particularly in tumors from left colon and rectum. Therefore, TLR4 expression by fibroblasts could be a useful prognostic marker in CRC.