Background: At present, there is still no ideal non-invasive biomarker for colorectal cancer (CRC) screening. Previously, we found serum synaptophysin like 1 (SYPL1) served as a potential biomarker for CRC diagnosis. However, whether fecal SYPL1 (fSYPL1) are more sensitive and specific for CRC remains unclear. Methods: We analyzed fSYPL1 in controls (n = 70), adenoma patients (n = 80), CRC patients (n = 150) and postoperative CRC patients (n = 25) by ELISA. Results: SYPL1 was stable in feces. The fSYPL1 levels were significantly higher in CRC patients than in either controls or adenoma patients (P < 0.0001). ROC curves showed that fSYPL1 performed superbly in distinguishing CRC patients from controls (AUC = 0.947; 95% CI: 0.920-0.974, P < 0.0001, sensitivity: 80.67%, specificity: 100.00%), which showed much stronger performance than the traditional biomarkers (FOBT, CEA and CA19-9). Meanwhile, the fSYPL1 level positively correlated with tumor size, tumor invasion, lymph node invasion and clinical stage (P < 0.05). In addition, the detection rate of fSYPL1 was high in early CRC (75.00% in stage I and II). The fSYPL1 levels in CRC patients declined substantially after surgery (P = 0.0002). By means of a lower cut off level, 73.58% of high-risk adenomas were detected. The combination of fSYPL1 and FOBT performed better than the combination of plasma SYPL1, CEA and CA199 in distinguishing CRC patients from controls. Conclusion: The fSYPL1 might be a potential biomarker for CRC screening, early diagnosis, prognosis prediction and therapeutic effect monitoring.