Serum levels of lipoprotein(a) [Lp(a)], an independent risk factor for coronary heart disease, are strongly influenced by genetic factors. To evaluate the effect of weight loss on serum Lp(a), 54 normolipidemic obese women were examined before and after a two-month weight reduction programme. A mean weight loss of 10.1 kg was associated with decreases of serum triglycerides, total cholesterol (TC), LDL-C, HDL-C, apo B and apo A-I (P = 0.0001 for all variables), but not Lp(a). However, initial Lp(a) values were related to Lp(a) responses during dietary intervention (P = 0.0001). In subjects with pre-treatment Lp(a) values above 30 mg/dl, a mean 26.3% decrease was observed with weight loss, while no change was found in subjects with low Lp(a) values at baseline (P = 0.007 for group comparison). Apo E polymorphism contributes to the variation in lipid levels in the general population and in the obese. The relative contributions of the apo E locus to the total variance of TC, LDL-C and Lp(a) at baseline in these obese women were estimated to be 3.3, 1.7 and 3.2%, respectively, which are less than previously reported in healthy adults. Pre-treatment TC was increased in subjects with the apo E 3/4 phenotype compared to those with the common apo E 3/3 phenotype (P = 0.03). Apo E polymorphism did not affect Lp(a) levels at baseline nor the changes in lipoprotein variables, including Lp(a), during weight loss. In conclusion, short-term substantial weight loss in normolipidemic obese women resulted in a lowering of Lp(a) only in individuals with pre-treatment Lp(a) levels above 30 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)