Allergic skin reactions of the delayed type may be conveniently considered to involve two distinct processes: first, induction of the sensitized state, and second, elicitation of the allergic reaction in the sensitized individual. With regard to the induction of sensitization, it is generally believed that low molecular weight substances (haptens) can function effectively in this respect if they combine in vivo with tissue constituents, presumably proteins. This belief, which had long been reasonably maintained on the basis of analogy with the conditions required for the production of antisera by haptens, achieved a high degree of plausibility as a result of the systematic studies of Landsteiner and Jacobs (1, 2).The question as to whether hapten combination with protein is involved in the second process, namely, elicitation of the reaction, has received little attention. In many studies of the elicitation process, haptens which are homologous in structure to the hapten used for inducing sensitization often have produced widely divergent reactions: some homologues have elicited skin lesions, while other have not (3)(4)(5). This diversity of responses has been interpreted quite consistently in terms of specificity arising from the configurational conformity of the elicifing compound to the sensitizing hapten, little attention being paid to other factors that might modify the responses. However, from a consideration of these earlier studies, it appeared possible that, in addition to configurational features, at least one other factor--namely, combination of the eliciting hapten with protein--might be involved in accounting for the diverse responses sometimes obtained in eliciting reactions with haptens which are structurally similar to the substance used for inducing sensitization. Accordingly, we have sought to determine with a group of 2,4-dinitrophenyl compounds whether combination with protein is important in determining the effectiveness of haptens in producing delayed allergic skin lesions in sensitized guinea pigs and men.