Background: Colorectal cancer (CRC) is one of the most common malignancies and a major cause of cancer-related death worldwide. Fecal occult blood tests (FOBT) are non-invasive colorectal cancer screening tests. In recent years plasma microRNAs (miRNAs) have shown great potential in early non-invasive cancer detection. Methods: FOBT (immunochemical) and a panel of 12 plasma miRNAs were tested in two independent groups: 57 CRC patients and 125 neoplasm free controls, in addition to 58 advanced adenoma patients and 67 neoplasm free controls. miRNA levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Plasma levels of 7 miRNAs (miR-18a, miR-20a, miR-21, miR-92a, miR-133a, miR-143, miR-145) differed significantly between CRC patients and neoplasm free controls. miRNA plasma levels did not differ between advanced adenoma patients and controls. For 7 dysregulated miRNAs in CRC patients, AUCs ranged from 0.585 to 0.632 for CRC detection, in comparison to an AUC of 0.857 for iFOBT. The combination of miR-133a and iFOBT achieved a higher AUC (0.894) than iFOBT alone. At 97.8% specificity, miRNAs showed much lower sensitivities than iFOBT, but the miRNA panel and iFOBT in combination detected CRC with a higher sensitivity than iFOBT alone. Conclusions: The diagnostic performance of miRNAs was poorer than iFOBT. Nevertheless, plasma miRNA profiles offer an innovative non-invasive approach for early CRC detection. The potential advantage of combining plasma miRNA profiles with iFOBT needs to be further studied in a larger cohort of patients.