AbstractImmunochemical faecal occult blood tests (I‐FOBT) detect more effectively advanced neoplasia than guaiac tests (G‐FOBT). The study aim was to compare the performance of an I‐FOBT whilst varying the positivity threshold and considering four analysis modalities: one sample was performed (MG1), two samples were performed and at least one sample was positive (MG2+), both samples were positive (MG2++) or the mean of the two samples' log‐transformed haemoglobin contents exceeded the cutoff (MG2m). Screening for colorectal cancer using both G‐FOBT and two samples' I‐FOBT was performed by an average‐risk population sample of 20,322 subjects. Among the 1,615 subjects with at least one positive test, 1,277 had a satisfactory colonoscopy result; 43 invasive cancers and 270 high‐risk adenomas were detected. The I‐FOBT was reinterpreted under each analysis modality (a random selection of one sample led to MG1). For all modalities, increasing the positivity threshold decreased sensitivity and increased specificity. The relative ROC curves (in reference to G‐FOBT) demonstrated similar performance for MG1 and MG2+, and improved performance for MG2m. MG2++ sensitivity was limited within the range of positivity thresholds evaluated. For any specificity, MG2m provided the highest sensitivity. For any sensitivity, MG2m provided the highest specificity. For any positivity rate, MG2m provided both the highest sensitivity and specificity. This study suggests the replacement of MG2+ by MG1 or, for even better performance, by MG2m provided that two samples are performed with similar participation (which should be explored). The targeted positivity rate could then be achieved by choosing the positivity threshold. © 2009 UICC