Vasoactive intestinal peptide (VIP), a major neurotransmitter of peripheral nerves, has been suggested to function in host defense by regulating local human immune function. Indirect evidence has been marshaled that VIP can function as a switch factor for IgA in human Ig isotype recombination. In this study we directly tested the ability of VIP to function as a factor driving human B cells into IgA producing cells by assessing its ability to induce switch circular DNA representing direct mu to alpha switching. In addition we determined the generation of alpha germ-line transcripts and measured the level of IgA protein produced. Stimulation with VIP and CD40 mAb induced IgA production by human IgD+ B cells while VIP or CD40 alone failed to do so. Stimulation of purified IgD+ B cells with VIP plus CD40 mAb induced generation of switch circular DNA representing in vitro driven isotype switching from mu to alpha. CD40 mAb alone induced alpha germ-line transcripts but not IgA switch circles. Thus VIP, a neurogenic factor, can induce alpha-specific switching in CD40-activated human B cells and may thereby play an important role in directing the humoral immune response at mucosal surfaces.