This study examined the hypothesis that l-cysteine supplementation can lower insulin resistance, glycemia, oxidative stress, and markers of vascular inflammation in type 2 diabetes using Zucker diabetic fatty (ZDF) rats as a model. Starting at the age of 6 weeks, ZDF rats were supplemented orally (daily gavage, 8 weeks) with saline placebo (D) or l-cysteine (LC; 1 mg/kg bw) and fed a high-calorie diet. Six-week-old rats without any supplementation were considered baseline (BL) rats. D rats showed elevated fasting blood glucose, glycated Hb, CRP, and MCP-1 compared with BL rats in which there was no onset of diabetes. LC supplementation significantly lowered blood levels of glucose (18%, p= 0.05), glycated Hb (8%, p= 0.02), CRP (23%, p= 0.02), MCP-1 (32%, p= 0.01), and insulin resistance (25%) compared with levels seen in saline-supplemented D rats. There was a decrease in plasma protein oxidation levels (p< 0.01); however, GSH levels were similar in LC and D groups. Although LC did not change blood hematocrit or levels of transaminases, it did lower alkaline phosphatase (29%, p= 0.01) levels in comparison to D. Western blotting analyses of liver showed increased activation of NF-kappaB and Akt (50% pNF-kappaB and 20% pAkt) in D compared with BL rats. LC supplementation inhibited these effects (17% pAkt, 18% pNF-kappaB). This is the first report showing that l-cysteine supplementation can lower glycemia and markers of vascular inflammation in diabetes apparently by preventing NF-kappaB activation in a diabetic animal model.