Caspase-1 processes the interleukin (IL)-1β and IL-18 inactive precursors to the biologically active cytokines that are known to have proatherogenic effects. The present study investigated the genetic variability of the CASP1 gene and plasma levels of caspase-1 in relation to cardiovascular risk. In Europeans, 3 tag SNPs captured 4 common haplotypes of the CASP1 gene. Among these, the A in6 allele of the G+7/in6A polymorphism was less frequent in 246 cases with myocardial infarction and a parental history of disease than in 253 controls free of familial history of disease (0.13±0.02 versus 0.20±0.02; P =0.005). However, in a larger case/control study (n=1774), these effects are borderline restricted to the UK population. In a prospective cohort of 1168 patients with coronary artery disease followed up during a median period of 6.0 years, the A in6 allele exhibited a borderline association with future cardiovascular death (hazard ratio [HR]: 0.64, 0.41 to 1.01; P =0.053) and was associated with lower serum IL-18 levels ( P =0.014). Baseline caspase-1 levels in the top quartile of the distribution were predictive of cardiovascular deaths (HR=3.62, 1.81 to 7.27; P =0.0003 compared with the bottom quartile). Finally, in vitro assays of allelic imbalance showed that the CASP1 haplotype carrying the A in6 allele was associated with a lower mRNA expression. These results indicate that caspase-1 levels are predictive of future cardiovascular death in patients with coronary artery disease. The role of CASP1 genetic variations in the susceptibility to myocardial infarction requires further investigation.