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Heat shock protein (HSP)70-2 is an important immunomodulatory protein induced in response to inflammatory stimuli. We assessed whether HSP70-2+1267 genotype influenced the risk of septic shock in a prospective cohort study of community-acquired pneumonia and whether HSP70-2+1267 genotype is a better predictor of septic shock than the genotype at lymphotoxin-α +250.Prospective cohort study.A large, nonprofit, private hospital system in Memphis, TN.Adults admitted with community-acquired pneumonia between 1998 and 2001. Septic shock was defined according to consensus criteria (American College of Chest Physicians/Society of Critical Care Medicine, 1992).Blood sampling.A total of 343 subjects were enrolled; 30 had septic shock. HSP70-2+1267 and lymphotoxin-α +250 genotype was determined using polymerase chain reaction and restriction enzyme digestion. HSP70-2+1267 AA genotype was the strongest predictor of septic shock (p = .0005; relative risk, 3.5). Lymphotoxin-α +250 AA genotype was also associated with an increased risk of septic shock (p = .002; relative risk, 2.7). Logistic regression analysis found only age (p = .04) and HSP70-2+1267 genotype (p = .006) were predictors of septic shock. The greatest risk of septic shock was associated with carriage of the HSP70-2+1267 A/lymphotoxin-α +250 A haplotype (p < .0001).HSP70-2+1267 genotype is a stronger predictor of septic shock in patients with community-acquired pneumonia than lymphotoxin-α +250 genotype.