The nonspecific (nonallergic) inflammatory activity of melittin, a protein toxin from honeybees, was correlated with specific amino acid sequences. Two different amino acid sequences of melittin were found to contribute to nonspecific inflammatory activities in guinea pig skin. Carboxy terminal peptide sequences of 7--10 amino acids induced immediate inflammatory reactions that reached maximum intensities by 15--30 min, then rapidly dissipated. The amino (N) terminal hydrophobic sequence, although not directly inflammatory, intensified the immediate reaction, causing a severe lesion evident by 2 h and characterized by massive polymorphonuclear leukocyte infiltration. A conceptual model of bee venom-induced inflammation in nonallergic individuals is suggested.