Background: Colorectal cancer (CRC) is one of the prevailing causes of cancer mortality in the world. A common screening test for CRC is based on the human hemoglobin immunochemical based fecal occult blood test (iFOBT), which consists in the detection of blood in the patient's stool. In addition to iFOBT, recent studies support the use of the gut microbiome as a biomarker for CRC prediction. However, these studies did not take into account the effect of blood itself on the microbiome composition, independently of CRC. Therefore, we investigated the microbiome of patients undergoing the iFOBT screening in order to determine the effect of blood alone. Our cohort consisted of patients who had no blood in their stools (n = 265) or did have blood but no underlying precancerous or cancerous lesions (n = 235). We also identified bacterial taxa specifically associated with the presence of blood in stools. Results: We observed significant differences in the intestinal bacterial composition that could be solely caused by the presence of blood in stools. More precisely, we identified 12 bacterial species showing significant differences in abundance between both our study groups. These species, Bacteroides uniformis, Collinsella aerofaciens, Eggerthella lenta and Clostridium symbiosum demonstrated increased abundance in the presence of blood. In contrast, the species Prevotella copri, Coprococcus eutactus and catus, Faecalibacterium prausnitzii, Roseburia faecis, Blautia obeum, Gemmiger formicilis and Clostridium celatum showed decreased abundance in patients with blood in their stools. Notably, we found multiple taxa that were reported in previous studies linking microbiome composition and diseases. Conclusions: We show that, in the absence of disease, blood in the stools has a major influence on the composition of the microbiome. Our data suggest that blood itself should be taken into consideration when investigating the microbiome signatures of intestinal diseases.