Background Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder. The aim of this study was to examine associations among genetic polymorphisms, SstI polymorphism of apolipoprotein CIII (ApoCIII) and Hind III polymorphism of lipoprotein lipase (LPL), environmental factors and risks of HTG. Methods and Results Two hundred and forty-nine southern Taiwanese aborigines were recruited for a cross-sectional study, which included 90 subjects with triglyceride (TG) >150 mg/dl (HTG) and 159 with TG ≤150 mg/dl (NTG). The frequencies of SstI major allele (S1) and minor allele (S2) of ApoCIII were 66.1% and 33.9% in HTG and 73.6% and 26.4% in NTG (p<0.1). In female subjects, the frequencies of the S2 allele was significantly higher in HTG (0.38) than NTG (0.27) (p<0.04). The frequencies of the LPL HindIII major allele (H+) and minor allele (H-) were similar between HTG (H+ 84.3%; H- 15.7%) and NTG (H+ 78.9%; H- 21.1%). In a multivariate adjusted logistic model, education ≤6 year (odds ratio (OR) =3.71, 95% confidence interval (CI): 1.24-8.13), Amis tribe (OR =3.08, 95% CI: 1.41-6.77), body mass index (BMI) ≥25 (OR =2.22, 95% CI: 1.18-4.16), starchy food consumption ≥3 times/week (OR =1.89, 95% CI: 1.00-3.59) and ApoCIII S2S2 genotype (OR =3.35, 95% CI: 1.10-10.19) were independently (p<0.05) associated with HTG risks. Among ApoCIII S1S1, S1S2 and S2S2 genotypes, ApoCIII and TG concentrations increased (p<0.01) in a dose-responsive manner. Conclusions The ApoCIII S2 variant and environmental factors, including education, tribal background, BMI and starchy food intake, modulate the risks of HTG in aboriginal Taiwanese. Interaction between genetic and environmental factors warrants further investigation. (Circ J 2006; 70: 1030 - 1036)