Background & Aims Rapidly progressing or missed lesions can reduce the effectiveness of colonoscopy-based colorectal cancer surveillance programs. We investigated whether giving fecal immunochemical tests (FITs) for hemoglobin between surveillance colonoscopies resulted in earlier detection of neoplasia. Methods The study included 1736 patients with a family history or past neoplasia; they received at least 2 colonoscopy examinations and were followed for a total of 8863 years. Patients were excluded from the study if they had genetic syndromes, colorectal surgery, or inflammatory bowel disease. An FIT was offered yearly, in the interval between colonoscopies; if results were positive, the colonoscopy was performed earlier than scheduled. Results Among the 1071 asymptomatic subjects (61%) who received at least 1 FIT, the test detected 12 of 14 cancers (86% sensitivity) and 60 of 96 (63%) advanced adenomas. In patients with positive results from the FIT, the diagnosis of cancer was made 25 months (median) earlier and diagnosis of advanced adenoma 24 months earlier. Patients who had repeated negative results from FIT had an almost 2-fold decrease in risk for cancer and advanced adenoma compared with patients who were not tested (5.5% vs 10.1%, respectively, P = .0004). The most advanced stages of neoplasia, observed across the continuum from nonadvanced adenoma to late-stage cancer, were associated with age (increased with age), sex (increased in males), and FIT result. The probability of most advanced neoplastic stage was lowest among those with a negative result from the FIT (odds ratio, 0.68; P < .001). Conclusions Interval examinations using the FIT detected neoplasias sooner than scheduled surveillances. Subjects with negative results from the FIT had the lowest risk for the most advanced stage of neoplasia. Interval FIT analyses can be used to detect missed or rapidly developing lesions in surveillance programs.