Variation in the PON1 and PON2 genes has been shown to be associated with coronary heart disease risk in adults of South Asian origin. In this group, low birth weight is also associated with coronary heart disease risk. We therefore hypothesized that variation in PON1 and PON2 genes may be associated with variation in birth weight. This relationship was examined in 290 consecutive Trinidadian neonates of different ethnic origins. We found that variation in PON2 was significantly associated with variation in birth weight in Trinidadian neonates of South Asian origin. Among the neonates of South Asian origin, those who were homozygous for PON2 A148/A148 had significantly lower birth weight, by approximately 200 g, compared with those with the other two genotypes (P < 0.05). For neonates of South Asian origin, PON2 A148/A148 homozygotes were significantly more prevalent in those comprising the lowest tertile for birth weight than those comprising the highest tertile (0.41 versus 0.24, P < 0.05). There were no significant associations of PON2 variation with any phenotype in other ethnic groups. We conclude that among neonates of South Asian origin, homozygosity for PON2 A148/A148, is associated with significantly lower birth weight. This suggests that genetic factors in the fetus may be important determinants of neonatal birth weight and possibly of more distal adult phenotypes, such as coronary heart disease.