Background: There is little information about the fecal immunochemical test (FIT) in familial-risk colorectal cancer (CRC) screening. Objectives: The objective of this article is to investigate whether FIT diagnostic accuracy for advanced neoplasia (AN) differs between average and familial-risk (first-degree relative) patients. Methods: A total of 1317 consecutive participants (595 familial) who collected one stool sample before performing a colonoscopy as a CRC screening test were included. FIT diagnostic accuracy for AN was evaluated with Chi-square test at a 20 mg hemoglobin/g of feces cut-off value. Finally, we determined which variables were independently related to AN. Results: An AN was found in 151 (11.5%) patients. The overall accuracy was not statistically different between both cohorts for AN (88.4%, 91.7%; p ¼ 0.051). At the cut-off stablished, differences in FIT sensitivity (31.1%, 40.6%; p ¼ 0.2) or specificity (96.5%, 97.3%; p ¼ 0.1) were not statistically significant. Finally, independent variables such as sex (male) (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.4-3.1), age (50-65, >65 years) (OR 2.1, 95% CI 1.1-4.3; OR 2.7, 95% CI 1.2-6.1), previous colonoscopy (OR 0.4, 95% CI 0.2-0.9) and FIT 20 mg/g feces (OR 17.7, 95% CI 10.8-29.1) were associated with AN diagnosis. Conclusions: FIT accuracy for AN detection is equivalent in average and familial-risk CRC screening cohorts.