Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial triglyceride‐rich lipoproteins (TRLs). We recently reported that livers from T2DM db/db mice markedly overexpress the heparan sulfate glucosamine‐6‐O‐endosulfatase‐2 (SULF2), an enzyme that removes 6‐O sulfate groups from heparan sulfate proteoglycans (HSPGs) and suppresses uptake of TRLs by cultured hepatocytes. In the present study, we evaluated whether Sulf2 inhibition in T2DM mice in vivo could correct their postprandial dyslipidemia. Selective second‐generation antisense oligonucleotides (ASOs) targeting Sulf2 were identified. Db/db mice were treated for 5 weeks with Sulf2 ASO (20 or 50 mg/kg per week), nontarget (NT) ASO, or phosphate‐buffered saline (PBS). Administration of Sulf2 ASO to db/db mice suppressed hepatic Sulf2 messenger RNA expression by 70%‐80% (i.e., down to levels in nondiabetic db/m mice) and increased the ratio of tri‐ to disulfated disaccharides in hepatic HSPGs (P < 0.05). Hepatocytes isolated from db/db mice on NT ASO exhibited a significant impairment in very‐low‐density lipoprotein (VLDL) binding that was entirely corrected in db/db mice on Sulf2 ASO. Sulf2 ASO lowered the random, nonfasting plasma triglyceride (TG) levels by 50%, achieving nondiabetic values. Most important, Sulf2 ASO treatment flattened the plasma TG excursions in db/db mice after corn‐oil gavage (iAUC, 1,500 ± 470 mg/dL·h for NT ASO versus 160 ± 40 mg/dL·h for Sulf2 ASO\P < 0.01). Conclusions: Despite extensive metabolic derangements in T2DM mice, inhibition of a single dys‐regulated molecule, SULF2, normalizes the VLDL‐binding capacity of their hepatocytes and abolishes postprandial hypertriglyceridemia. These findings provide a key proof of concept in vivo to support Sulf2 inhibition as an attractive strategy to improve metabolic dyslipidemia. (HEPATOLOGY 2012;55:1746–1753)