The relative contribution of the classical and alternative pathways in complement activation was quantified in 20 patients with systemic meningococcal disease. The activation products C4bc, C4bd, and Bb, indicating classical and alternative pathway activation, were measured with neoepitope-specific EIAs. Ten patients with persistent septic shock had significantly higher levels of Bb (P<.001), but not of C4bc (P=.43), than did 10 patients without septic shock. The Bb levels were significantly correlated with C3 activation products (C3bc; r= .72, P=.002), terminal SC5b-9 complement complex (TCC; r=.89, P<.001), and plasma lipopolysaccharides (LPS; r=.69, P= .01). There was no such association for C4bc versus C3bc, TCC, or LPS. Serially collected samples demonstrated activation of both pathways in patients with or without shock. Intervention strategies to stop the massive complement activation in fulminant meningococcal septicemia should include therapeutic principles that inhibit the alternative pathway.