Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. Inappropriate immune responses as seen in chronic inflammatory conditions as well as immunodeficiency states confer increased risk of developing cancer. This aim of this study was to evaluate the effect of immune dysfunction on the characteristics of LS associated cancers. Methods: This was a retrospective analysis of LS patients and carriers at two institutions listed above. We evaluated mutational profiles, immune status, age of onset of first and subsequent cancers in this cohort. Results: 106 patients with mutations consistent with LS were included. 72 patients had at least one cancer while 34 were carriers. 44% patients were Caucasian female, 18% white males, 14% African American males, 11% African American females and 10% Hispanic females. Colon cancer (CRC) was the most common cancer (44%) and PMS2 was the most common mutation, noted in 35 patients (33%). Of the 72 patients with LS associated cancer, 18 patients were either immunosuppressed or had an autoimmune condition. Of the 10 patients who had an autoimmune condition ,7 had multiple cancers. Of the 9 patients who were immunosuppressed, 5 had multiple cancers. Out of a total of 18 out of 72 patients who had multiple cancers, 12 (66%) had either an autoimmune condition or were immunosuppressed. CRC was the index cancer in 42% and breast in 33% of patients with multiple cancers. Patients with MSH2 were most likely to have an immune related condition (32%) and accounted for 41% of patients with multiple cancers. The median age of first cancer in this group was 46 years while it was 48.5 years in the population without immune dysfunction (p = 0.2). There was a high prevalence of breast cancer (24%) as a LS associated cancer in our study population. 66% of the patients with PMS2 mutation had breast cancer with a median age of onset of 48 years (62 years for sporadic cancer). Conclusions: Our study is the first to look at the effect of immune dysfunction in LS patients. Immune dysfunction was associated with a higher rate of multiple cancers and was more commonly associated with the MSH2 mutation. It also highlights importance of aggressive screening for breast cancer in LS patients (especially with PMS2 mutation).