We report the distribution of the APOB signal peptide polymorphism in 5 native populations of South America: 2 samples of Mataco and 1 sample each of Pilagá and Toba from the Argentinian Chaco and 1 sample of Ache from the Paraguay forest. A randomly selected subsample of a previously studied sample from the Cayapa of Ecuador (Scacchi et al. 1997) was reanalyzed to investigate probable differences attributable to sampling, laboratory techniques, or interobserver error. The polymorphism observed in the signal peptide region of the APOB gene among native populations of South America exhibits the same range of variation found among geographic continental populations, confirming the high genetic heterogeneity of South Amerindians. Extremes in the allele prevalences were found among the Mataco and Ache, populations not far apart geographically. The small differences in genotype and allele frequencies between the subsample of the Cayapa analyzed here and the original Cayapa sample and between the 2 Mataco samples were not statistically significant and most likely were due to sampling error.