The pathogenesis of alpha-hemolytic streptococcus shock syndrome (SS), a life-threatening complication in neutropenic patients following aggressive chemotherapy that is caused by viridans streptococci, is unknown. We measured serum concentrations of proinflammatory and antiinflammatory cytokines and T cell activation markers in two patients with lethal alpha-hemolytic streptococcus SS. The results were compared with those for controls, two neutropenic patients with uncomplicated bacteremia due to gram-positive organisms and four patients with neutropenia and bacteremia due to gram-negative organisms (two of whom had lethal septic shock). In patients with alpha-hemolytic streptococcus SS, levels of interleukin (IL) 1 were undetectable, levels of tumor necrosis factor (TNF) alpha were only slightly elevated, and IL-6 was the only proinflammatory cytokine that was found in high concentrations and had a late peak level at the time of clinical deterioration. IL-6 levels were much higher in patients with alpha-hemolytic streptococcus SS than in controls with uncomplicated bacteremia due to gram-positive organisms but were comparable with those in controls with bacteremia due to gram-negative organisms. Soluble TNF receptor fragments and IL-1 receptor antagonist apparently were not protective despite high serum concentrations.