Genetic studies carried out mainly in European and European-derived populations have shown that common polymorphisms in genes coding for apolipoproteins are significant determinants of serum lipoprotein-lipid levels variation. However, except for a few sporadic studies, the distribution of apolipoprotein polymorphisms and their association with serum lipoprotein-lipid levels have not been evaluated systematically in African or African-derived populations. In this investigation we have studied five apolipoprotein polymorphisms, including APOA1/MspI-75 bp, APOA1/MspI+83 bp, APOC3/PvuII, APOE, and APOH in 786 Africans (493 men, 293 women) from Nigeria. The sample is comprised of Nigerian civil servants consisting of 462 junior staff (less affluent) and 324 senior staff (more affluent) where staff status is a correlate of their socioeconomic status. We first examined genetic associations in the total sample stratified by gender to determine the role of apolipoprotein polymorphisms in affecting serum lipid profile in the general population, and then by staff status to evaluate possible gene-environment interactions. In the total sample, the APOC3/PvuII polymorphism showed significant effect on HDL-cholesterol (P = 0.029) and HDL3-cholesterol (P = 0.009) in women, and the APOE polymorphism was significantly associated with total cholesterol (P = 0.031) and LDL-cholesterol (P = 0.0006) in women. Multiple regression analyses showed that the APOC3/PvuII polymorphism accounts for about 2 and 3% of the variation in HDL-cholesterol and HDL3-cholesterol, respectively, in women; while the APOE polymorphism accounted for about 5 and 6% of the variation in total- and LDL-cholesterol, respectively, in women. Whereas the association of the APOE polymorphism was independent of the staff status, the significant affect of the APOC3/PvuII polymorphism on HDL- and HDL3-cholesterol was confined to senior staff women where it explained about 7% of their variation. We also observed an interaction between staff and the APOH polymorphism in affecting cholesterol levels. The APOH polymorphism showed significant association with total cholesterol (P = 0.010) and LDL-cholesterol (P = 0.016) in senior staff women and explained about 7 and 5% of their phenotypic variations, respectively. These data indicate that gene-environment interaction may play an important role in affecting serum lipid profile in African populations.