We recently obtained evidence of long-term adaptation of blood lipids to changes in intakes of carbohydrate and fiber in subjects with type 2 diabetes. We determined the effect of increased carbohydrate and fiber intakes on serum short-chain fatty acids (SCFAs) and the relation between changes in serum acetate and changes in blood lipids. Subjects with type 2 diabetes (n = 62) were randomly assigned to receive approximately 10% of energy from low-fiber breakfast cereal (LF diet), high-fiber breakfast cereal (HF diet), or monounsaturated fatty acids (MUFA diet) for 6 mo. Carbohydrate intakes were higher in the LF and HF groups than in the MUFA group (54% compared with 43%), and more fiber was consumed by the HF group (approximately 50 g/d) than by the LF or MUFA group (approximately 23 g/d). Fasting serum SCFAs did not change significantly over the first 3 mo. Between 3 and 6 mo, serum acetate tended (NS) to decrease in the LF group (from 69 +/- 4 to 59 +/- 5 micromol/L) and increase in the HF group (from 100 +/- 18 to 107 +/- 17 micromol/L), with no significant change in the MUFA group. Serum butyrate did not change significantly in the LF or MUFA group but increased in the HF group (from 2.5 +/- 0.5 to 3.1 +/- 0.6 micromol/L; P < 0.001). Changes in serum acetate from 0 to 3 mo were not related to changes in lipids. However, changes in serum acetate from 3 to 6 mo were positively related to changes in the ratio of total to HDL cholesterol (P = 0.041) and in fasting (P = 0.013) and postprandial (P = 0.016) triacylglycerols. In subjects with type 2 diabetes, changes in serum SCFAs in response to changes in carbohydrate and fiber intakes took many months to occur, and the changes in serum acetate were significantly related to the long-term adaptive changes in blood lipids.