Abstract The DECREASE SSI Trial (Decolonization to Reduce After-Surgery Events of Surgical Site Infection) Colon and small bowel surgery are high-volume, high-cost surgeries performed in over 675,000 patients in the United States each year. These surgeries carry one of the highest surgical site infection (SSI) rates, with estimates of 11-45%, or 2- to 3-fold higher than nationally reported rates, when comprehensive surveillance efforts are used, such as in clinical trials. Comprehensive tracking also uncovers a disproportionate amount of post-discharge incisional SSIs. These incisional SSIs are strongly tied to patient anxiety, stress, embarrassment, dissatisfaction, and lower quality of life scores. Mounting evidence shows that social and economic disadvantage can adversely affect the risk of SSI, likely due to the differential ability to protect a fresh incision from infection after hospital discharge. The Decolonization to Reduce After-Surgery Events of Surgical Site Infection (DECREASE SSI) Trial will test the value of adding a post-operative intervention to current pre-operative and intra-operative prevention practices. The DECREASE SSI Trial is a multi-site pragmatic randomized controlled clinical trial comparing routine post- discharge wound care to a post-discharge decolonization regimen of chlorhexidine bathing and nasal iodophor to prevent SSI events in the 30 days following discharge for open colon and small bowel surgery. If successful, this trial will provide a simple prevention measure for the 675,000 persons who undergo non-laparoscopic surgery involving the small and large intestines each year.