Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mellitus. Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variability in PLA2G2A were identified and distinguished six common haplotypes (frequencies > 5%). In the 523 Caucasian T2D patients, levels of sPLA(2)IIa, independent of CRP, were negatively correlated with total antioxidant status (P = 0.003) and high-density lipoprotein cholesterol (P = 0.006) in men and correlated with CAD status in women (P = 0.002) (Odds ratio of top two tertiles versus bottom = 2.50) [95% CI (1.13-5.53) P = 0.024]. Overall, tSNP haplotypes showed a highly significant association with sPLA(2)IIa levels (P < 0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA(2)IIa levels [3.25 ng/ml (+/- 0.14)] compared with the combined other haplotypes [2.13 ng/ml (+/- 0.09), P < 0.00001]. Five of the six tSNPs were associated with significant effects on sPLA(2)IIa levels but the raising haplotype could not be distinguished by a single tSNP and none are likely to be functional. These data confirm the relationship between elevated sPLA(2)IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA(2)IIa levels will help clarify the causality of this association.