Background: Cluster of differentiation 26 (CD26), also known as dipeptidyl peptidase IV (DPP4), is a multifunctional cell surface protein expressed in most cell types. As a complicated molecule with pleotropic effects, CD26/DPP4 can act as either a tumor suppressor or activator, depending on the cancer type and tumor microenvironment. Nonetheless, an enlarging body of pre-clinical evidence supports an association between CD26/DPP4 and tumor invasion and metastasis. CD26/DPP4 has thus been proposed as a target in the treatment of certain malignancies. In this study, we retrospectively analyzed diabetic patients (pts) with colorectal and airway malignancies to examine the effect of DPP4-inhibitors on progression free survival (PFS). Methods: We performed a multi-center retrospective review of pts with advanced (stage 3 or 4) colorectal or airway (lung, head and neck) cancer and reviewed the PFS of their respective malignancy on DPP4 inhibitors. All pts were diabetic on anti-hyperglycemic therapy and all received standard chemotherapy. Control group included pts on metformin and a sulfonylurea, and study group included pts on metformin and a DPP4 inhibitor. Fisher exact test was performed for univariate analysis and a multivariate regression logistic model was performed to calculate statistical significance. Results: Ninety-six patients were eligible to be included in the study. 18.4% of pts treated with DPP4 inhibitors had progression of their malignancy, compared to 48.1% of pts in the control group with an Odds Ratio 0.203 (95% CI: 0.063-0.646) and p-value 0.007. There was a statistically significant improvement in PFS in the study group (medium follow up of 18.5 months) when compared to control group (median follow up of 26 months) with a Hazard Ratio 0.423 (95% CI: 0.21-0.84) and p-value 0.014. Overall survival was improved but not significantly (p = 0.11). Conclusions: Exposure to DPP4 inhibitors in pts with diabetes and advanced colorectal or airway cancers led to statistically significant improvement in PFS. Further investigation with prospective randomized design is needed to validate the relationship between DPP4 inhibition and progression of malignancy.