Coronary heart disease (CHD) is increasing in developing countries, particularly in urban areas. The impact of urbanization and apolipoprotein (apo) A-IV genetic polymorphism on plasma lipoproteins was studied in 222 men and 236 women from rural and urban Costa Rica. The apoA-IV allele frequencies were 0.937 for apoA-IV-1 and 0.062 for apoA-IV-2, Significant interactions between the apoA-IV polymorphism and area of residence (rural versus urban) were detected for HDL cholesterol (P = .003), apoA-I (P = .05), LDL particle size (P = .01), and LDL/HDL cholesterol ratio (P = .005). Urban compared with rural carriers of the apoA-IV-2 allele had significantly lower plasma HDL cholesterol (0.95 versus 1.17 mmol/L) and apoA-I (980 versus 1140 mg/L), a significantly higher LDL/HDL cholesterol ratio (3.35 versus 2.39), and significantly smaller LDL particles (258 versus 263 A). In contrast, no significant rural-urban differences for these parameters were found in apoA-IV-1 homozygotes. Regardless of their apoA-IV phenotype, urban residents consumed more saturated fat (P = .02) and smoked more cigarettes per day (P = .03) than rural residents. A significant interaction between saturated fat intake and apoA-IV phenotype was found for HDL cholesterol (P < .0003) and LDL/HDL cholesterol ratio (P < .003). Increased saturated fat intake (13.6% versus 8.6% of calories) was significantly associated with 6% higher HDL cholesterol and no change (0.7%) in LDL/HDL cholesterol ratio in apoA-IV-1 homozygotes and with 19% lower HDL cholesterol and 37% higher LDL/HDL cholesterol ratio among carriers of the apoA-IV-2 allele. Smokers (> or = 1 cigarette per day) had significantly lower HDL cholesterol (P < .005) and apoA-I (P < .01) concentrations than nonsmokers (< 1 cigarette per day), particularly among carriers of the apoA-IV-2 allele (-19% and -13%) compared with apoA-IV-1 (-4% for both). After taking these lifestyle characteristics into account, the areas of residence by phenotype interactions for plasma lipoprotein concentrations were no longer statistically significant. Lifestyles associated with an urban environment, such as increased smoking and saturated fat intake, elicit a more adverse plasma lipoprotein profile among Costa Rican carriers of the apoA-IV-2 allele than in apoA-IV-1 homozygotes. Therefore, under the conditions studied, persons with the apoA-IV-2 allele may be more susceptible to CHD.