Smoking is one of the main risk factors for cardiovascular disease. The smokers exhibit different degrees of insulin resistance. The pathway of acylation-stimulating protein (ASP) and its specific receptor, C5a-like receptor 2 (C5L2), involves in the effective clearance of plasma glucose and triglyceride. ASP and insulin play similar but distinct roles in adipose metabolism. High level of ASP is indicative of ASP resistance and insulin resistance. Low level of ASP indicates increased insulin sensitivity. We proposed that the abnormality of ASP–C5L2 pathway contributes to insulin resistance in smokers.