Both insulin resistance and decreased insulin secretion are major features of the pathophysiology of type 2 diabetes. Inflammatory pathways are found to be critical in mechanisms underlying insulin resistance, which is a major determinant of increased risk of cardiovascular complications in type 2 diabetes, and so, it is a potential therapeutic target. Thiazolidinediones (e.g., rosiglitazone) act primarily as insulin sensitizers and were discovered to have anti-inflammatory effects leading to reevaluation of their potential use in treatment of diabetes. Acetyl salicylic acid (aspirin), which is currently recommended for cardiovascular disease (CVD) or even CVD risk factors, is shown to ameliorate diabetic process. This work aimed to study correlation between homeostasis model assessment estimate of insulin resistance (HOMA-IR) with serum levels of inflammatory markers tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), C-reactive protein (CRP), and free fatty acids (FFAs) in experimental model of induced type 2 diabetes in rats, with evaluation of effects of rosiglitazone and aspirin (low or high dose), alone or in combination. There is significant elevation of insulin resistance and serum levels of fasting glucose, insulin, TNF-alpha, IL-6, CRP, and FFAs in the diabetic group when compared to the normal group, with positive significant correlation between levels of each of TNF-alpha, IL-6, CRP, and FFAs with insulin resistance (HOMA-IR). Administration of rosiglitazone, low-dose aspirin, or high-dose aspirin to diabetic rats caused nonsignificant lowering in insulin level with significant reduction of levels of other parameters when compared to the diabetic group. Also, there is no significant difference in the measured parameters between diabetic rats administered a combination of rosiglitazone with high-dose aspirin and those administered a combination of rosiglitazone with low-dose aspirin. It was concluded that aspirin and rosiglitazone offer unique approaches for treatment of type 2 diabetes due to their insulin-sensitizing and anti-inflammatory properties, and their combination was found to provide augmented beneficial effects. Also, in view of the potential dose-dependent adverse effects of aspirin, with no achievement of further benefit by high dose in this study, it is strongly recommended to use low-dose aspirin as a safe and effective medication for diabetes.