Background: Although African Americans (AA) have the highest colorectal cancer (CRC) incidence and mortality of all populations in the United States, no studies have determined cancer risk and mismatch repair (MMR) genes mutation spectrum in LS patients of AA ancestry and the contribution of this syndrome to cancer disparities. Thus, the aims of this study are: (1) to describe LS cancers in AAs; (2) to investigate the mismatch repair (MMR) gene mutation spectrum in AA families with LS; (3) to determine how Amsterdam II criteria, revised Bethesda guideline, and PREMM(1,2,6) model perform for predicting MMR gene mutations in this population. Methods: Pedigrees of AA families with deleterious mutation or suspected deleterious mutation in MMR genes from five US referral centers were analyzed for personal and familial clinical cancer histories. Results: Twenty-four AA families were identified, of which 22 had deleterious mutations (15 MLH1, 4 MSH2, 2 MSH6, 1 PMS2) and 2 had suspected deleterious mutations (1 MLH1, 1 MSH2). Three recurrent mutation were found in MLH1(677G>A, IVS1-2A>G, IVS4-1G>A), accounting for 25% of all mutations. Of 24 probands, 58% were female and 96% had personal history of cancer. The median age at first primary tumor was 42yrs (range 28-57) and 50% developed more than 1 primary tumor. The majority of probands (79%) had CRC (median age of onset – 42yrs [range 31-61]), of which 26% had at least 2 CRC primaries. Endometrial cancer developed in 50% of the women (median age of onset – 51yrs [range 32-57]). Amsterdam II and Bethesda criteria were met in 63% and 88% of the individuals, respectively. Median score by PREMM(1,2,6) model was 54% (range 12.9-99.8). Conclusions: To our knowledge, this is the largest series of AA families with LS reported to date. Earlier age of onset for CRC at 42yrs (previously reported ~45 yrs) is suggested. The majority of mutations were found in MLH1 (67%), including three recurrent mutations. A 10% cutoff for PREMM(1,2,6) predictive model identified all mutation carriers. Larger studies are warranted to confirm the differences observed in age of CRC onset in this population.