Background: Smoking is associated with increased postprandial hypertriglyceridemia (PPT). Inflammation and insulin resistance are potential "drivers" for this phenomenon. We tested whether inflammatory patterns and/or insulin resistance explain the effect of smoking on PPT. Methods and results: Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 1036, age 49 ± 16 y) were included. Each participant was asked to suspend use of lipid-lowering drugs for 3 weeks and was given a high-fat milkshake (83% fat and 700 kcal/m2). Triglyceride concentrations at 0, 3.5 and 6 h after the fat load were measured. Inflammatory markers were measured at baseline. Principal component analysis was used to derive inflammatory patterns from individual inflammatory markers (hsCRP, IL2 soluble receptor-α, IL6, TNF-α and MCP1). Insulin resistance (IR) was estimated using the HOMA equation. Repeated measures-ANOVA was used for analyses. Two inflammatory patterns, namely CRP-IL6 pattern and MCP1-TNF-α pattern, were derived. We found significant main (smoking and time) and interaction (smoking × time) effects (P < 0.01) for triglycerides. The multivariate-adjusted triglyceride (mg/dL) concentrations (mean ± S.E.M.) for never, past and current smokers were 127.38 ± 1.04, 119.82 ± 1.05 and 134.92 ± 1.08 at 0 h; 229.42 ± 1.04, 238.39 ± 1.05 and 293.94 ± 1.08 at 3.5 h; and 194.63 ± 1.04, 208.38 ± 1.05 and 248.27 ± 1.08 at 6 h after the fat load, respectively. Smoking remained significant after adjusting for HOMA-IR and/or inflammatory patterns which showed independent associations with PPT (P < 0.05). Conclusions: These data confirm impaired metabolism of fat among smokers and suggest that mechanisms other than inflammation or insulin resistance may explain the observed hypertriglyceridemia among smokers. © 2008 Elsevier Ireland Ltd. All rights reserved.