Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR = 15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho = 0.32, q = 0.11) was driven by men (interaction P = 0.0055). rs73161338 was associated with INSIG1 expression changes (P = 5.4 × 10 − 5 ) and TG response in two statin clinical trials (P = 0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P = 5.6 × 10 −6 ). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.