Participation in a health promotion program for 192 overweight and obese adults with mental retardation was associated with behavior change resulting in reduction of body mass index-BMI (weight in kg, divided by height in meters, squared) by the end of the program. We analyzed the mediating and intermediate factors contributing to weight reduction and found knowledge and exercise to be the primary contributing factors. The curriculum emphasized exercise, nutritional choices, and stress reduction. Participation in the program was associated with a reduction of 0.8 BMI or approximately 2.3 kg for 26% of the participants. Increased knowledge about healthy diet and exercise was the most significant mediator of program impact on BMI.