Objectives: To examine the association of perceived discrimination with participant retention and diabetes risk among American Indians and Alaska Natives. Methods: Data were drawn from the Special Diabetes Program for Indians-Diabetes Prevention Demonstration Project (N = 2553). Results: Perceived discrimination was significantly and negatively associated with short-term and long-term retention and diabetes risk without adjusting. After controlling for socioeconomic characteristics and clinical outcomes, perceived discrimination was not associated with retention but was significantly associated with less improvement in body mass index (BMI) and high-density lipoprotein (HDL) cholesterol. Every unit increase in the perceived discrimination score was associated with 0.14kg/m2 less BMI reduction (95% CI: [0.02, 0.26], p = 0.0183) and 1.06mg/dl lower HDL at baseline (95% CI: [0.36, 1.76], p = 0.0028). Discussion: Among racialized groups, improving retention and health in lifestyle interventions may require investigating perceived discrimination and the broader context of structural racism and colonialism.