Mannose-binding protein (MBP; mannan-binding protein, mannan-binding lectin) is a member of the collectin family of proteins and is thought to be important in innate immunity. We have previously shown high frequencies of two distinct mutations in codon 54 and codon 57 of exon 1 of the MBP gene in non-African and African populations, respectively. These result in low levels of the protein and an opsonic deficiency but the frequencies also suggest some selective advantage for low MBP levels. A third mutation in codon 52 occurs at a much lower frequency. We have now extended our earlier studies to other populations. In the south-west Pacific (Papua New Guinea and Vanuatu) neither the codon 52 nor the codon 57 mutation was detected and the codon 54 mutation was significantly less common (gene frequencies of 0.07 and 0.01, respectively) than in other non-African populations (gene frequencies 0.11-0.16). This could be explained by relatively recent admixture. The ancestral Melanesian population probably diverged some 50,000-60,000 years ago and our data suggest that the codon 54 mutation may have occurred after that even but before the divergence of European-Asian groups (40,000 years ago). Two further sub-Saharan populations were also studied: a group of Xhosa from South Africa were similar to Gambians, with a high gene frequency for the codon 57 mutation (0.27) and no evidence of the codon 52 or 54 mutations. In contrast, San Bushmen from Namibia had low frequencies of both the codon 57 mutation (0.07) and the codon 54 mutation (0.03). Again the codon 52 mutation was not found. This pattern is unique amongst sub-Saharan populations studied to date and suggests that this population may have been subjected to different selective pressures.