Colorectal cancer (CRC) is immunogenic, with intratumoral Type 1 T-cells forecasting favorable prognosis (1). Furthermore, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown in multiple observational studies and clinical trials to be associated with reduction in risk of several cancers (2, 3), particularly malignancies of the gastrointestinal tract. These cancer preventive properties are especially evident in the colon, where NSAIDs reduce pre-invasive lesions as well as invasive cancer (4). Evidence suggests that adenomatous polyps are driven by microbe-dependent inflammation (5), reinforcing the notion that the anti-cancer role played by NSAIDs occurs via their anti-inflammatory mechanisms, i.e. suppression of prostaglandin E2 (PGE2) production by inhibition of cyclooxygenases (COX1 and 2). In addition, preliminary evidence suggests that NSAIDs may also oppose carcinogenesis by eliciting anti-cancer Type 1 cellular immune responses (6-9). As an example, at the interface between anti-inflammatory and immunologic activity, possible mechanisms by which NSAIDs may limit carcinogenesis are by preventing PGE2-mediated inhibition of dendritic cells and inhibiting PGE2-dependent redirection of monocytes from functional TH1-inducing antigen presenting cells into immunosuppressive myeloid derived suppressor cells (MDSCs) (10). This additional domain of NSAID activity suggests that combining agents such as aspirin with immunologic interventions holds promise in the area of prevention. Vaccines have a number of advantages in cancer prevention, compared to therapy (11, 12). They are generally non-toxic and limited intervention can elicit long-lasting immunologic memory, both key features of any intervention in a healthy, though high-risk, individual. Furthermore, the microenvironment of pre-malignant lesions that define “high risk” is less likely to have undergone extensive immunoediting and should have a lesser degree of immunosuppressive elements than that of invasive cancerous lesions (11, 13). In the high-risk colon (including genetic syndromes and colons containing premalignant lesions/adenomas), vaccines designed with appropriate antigenic epitopes are anticipated to reduce progression to invasive cancer, given the immunogenic nature of cancers in this tissue. Preliminary data support this hypothesis, showing that immunization with antigens derived from genes that are overexpressed and function as “drivers” in colon carcinogenesis can inhibit tumor development (14). COX2 and CDC25B, for example, have been shown to prevent development of polyps in 50% of APCMin mice and significantly decrease polyp formation in the other 50%. The commonality of mechanisms underlying the cancer preventive effects of NSAIDs and vaccines suggests that combining the two approaches may provide synergy, with tumor/adenoma reduction as a primary efficacy endpoint. Investigation of the mechanisms underlying any observed benefits of these interventions in CRC risk reduction will require evaluation of appropriate immunologic endpoints, cellular and possibly humeral.