Objective: The authors' purpose in this study was to compare the effects of macronutrient intake on systemic glucose levels in previously sedentary participants who followed 1 of 4 diets that were either higher protein or high carbohydrate, while initiating an exercise program. Participants and Methods: The authors randomly assigned 94 sedentary participants to 1 of 4 diet groups consisting of Diet 1 (55% carbohydrate, 30% fat, 15% protein), Diet 2 (55% carbohydrate, 30% fat, 15% protein and caloric restriction), Diet 3 (40% carbohydrate, 30% fat, 25% protein), and Diet 4 (40% carbohydrate, 30% fat, 25% protein and caloric restriction) and followed recommended aerobic exercise prescriptions. Results: Repeated measures analyses of variance (ANOVA) revealed a significant time factor (p = 0.021) but no significant differences between diet groups (p = 0.207). A trend was evident in the higher protein groups, with a 5.2% decrease in glucose levels with Diet 3 and 5.0% with Diet 4. Although glucose levels changed over time with the greatest changes in the 2 higher protein diets, levels were not significantly different within participants. Conclusions: The results of the study indicate that systemic glucose availability was affected by higher protein consumption in Diet 3 participants, with the same trend in Diet 4 participants, although nonsignificant. These findings demonstrate that consuming a lower carbohydrate diet for 12 weeks can possibly change systemic glucose levels. (Contains 2 tables and 1 figure.)