Background: MSI status remains an important clinical and prognostic marker and has been associated with better outcomes in CRC. AA patients are known to have more aggressive CRC at diagnosis and worse survival. The significance of MSI in this population is not well characterized. We analyzed effect of MSI status in AA patients, its effect on survival and response to 5-FU. Methods: We retrospectively analyzed 143 AA patients with CRC, who had MSI/MMR testing performed and were treated at Grady Memorial Hospital. We examined MSI status and expression of KRAS, BRAF V600, MLH1, MSH2, MSH6 and PMS2 in surgical specimens. Results: 19 patients had MSI-H. One presented with stage 1, 13 (68%) with stage 2, 3 (16%) with stage 3 and 2 with stage 4 disease. In this group 3 had Node positive disease, 1 had LVI, while 13 (68%) were stage 1 or 2 with no high-risk features. In the MSS group, 10 patients were stage 1, 38 stage 2 (30%), 42 stage 3 (33%) and 34 (27%) had stage 4 disease. In the MSI-H group 10 patients received 5-FU (including 6 stage 2 patients). The MSS group had 19 stage 2 patients out of a total of 86 patients treated with 5-FU. At the time of analysis 3 patients (15%) had died in the MSI-H group and 13 (10%) in the MSS group. Median OS was 26 months in the MSI-H and 28.5 months in the MSS group (not statistically significant). Similarly, progression free survival (p = 0.3) and overall survival (p = 0.6) was not affected by MSI status in all stages of. Patients treated with 5-FU (10 in MSI-H and 86 in MSS group) showed no difference in OS (p = 0.693) in the entire group or when stage 2 disease was analyzed separately (p = 0.403). Conclusions: We present the largest analysis of AA population with CRC and look at the impact of MSI status on survival and effect of therapy with 5-FU. Our study showed that in the AA population, MSI status had no impact on PFS or OS. At the same time, we saw similar benefit of 5-FU, regardless of the presence of MSI-H or MSS in this patient population. Since the AA patient population has historically had worse outcomes and is underrepresented in CRC clinical trials, further studies are needed in these patients to better tailor therapy