Several conflicting reports on the ability of IgG4 to mediate type I allergic reactions have appeared lately. We have developed a model system for testing this possibility, using passive sensitization of basophil leucocytes from normal individuals. At first, the system was optimized with regard to donor cells and anti-IgG4 antibody: among 3 normal individuals with cells showing high, medium and low responses to anti-IgE, only the high responder showed a reproducible, but low response to anti-IgG4. This response was consistent when testing anti-IgG4 from different sources, and could be potentiated by a phorbol ester TPA, although not up to the level of anti-IgE. The cells from the high responding donor and a monoclonal anti-IgG4 were selected for further studies. Serum pools from patients allergic to house dust mite (Dermatophagoides pteronyssinus) were used for passive sensitization. The pools contained allergen-specific IgE with or without concomitant IgG4 of the same specificity. The sensitized basophils reacted to anti-IgE and allergen, but to anti-IgG4 only to a small extent. However, when these serum pools were fractionated by affinity chromatography, only the IgE fractions and not the IgG4 fractions made the cells reactive towards specific allergen. It was still possible to elicit a reaction by triggering IgE with anti-IgE, whereas only a small reaction was seen, when IgG4-sensitized basophils were provoked with anti-IgG4. We conclude that IgG4 does not sensitize normal basophils.