Interleukin (IL)-6 plays an important role in the pathogenesis of coronary heart disease (CHD). Two functional polymorphisms in the IL-6 promoter have been identified (-174G>C and -572G>C), with both the rare alleles being associated with higher plasma levels of IL-6 after bypass surgery and one of them (-174G>C) associated with CHD risk. We have studied the contribution of these polymorphisms to CHD risk in the West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. Four hundred ninety-eight cases (consisting of individuals experiencing a cardiovascular event during 4.8 years of follow-up) and 1109 controls (individuals matched for age and smoking habits) were genotyped. In the placebo group, there was no significant evidence of higher risk associated with the -174CC genotype compared with the GG+GC group. However, in the pravastatin-treated group, CC homozygotes had a significantly lower risk of CHD compared with the GG+GC placebo group (odds ratio 0.46, 95% CI 0.27 to 0.79), and this remained statistically significant after adjustment for classic risk factors. Compared with the GG+GC group, men with the CC genotype had modestly, but not significantly, higher baseline levels of IL-6, C-reactive protein, or fibrinogen but showed a significantly greater fall in LDL cholesterol with statin treatment (P=0.036). The -572G>C polymorphism was not significantly associated with any plasma trait or CHD risk. Thus, in subjects under pravastatin treatment, the -174CC genotype was associated with a lower risk of CHD. These results demonstrate the importance of the inflammatory system in determining the risk of CHD and support the nonlipid effect of statins on risk.