Guinea pig anaphylactic responses usually involve IgG1 antibodies. Although IgE antibody production has been accomplished, a reliable and sustained method for production has not been described. We have investigated a method of enhancing IgE antibody production in guinea pigs. The criteria for IgE production were homologous passive cutaneous anaphylaxis (PCA) antibody activity that passed an affinity column of rabbit anti-guinea pig IgG1, heat lability (56 degrees C for 3 hr), and a long sensitization period in skin (7 days). Hartley guinea pigs were primed and boosted monthly with 1 microgram Picryl-Ascaris plus 1 mg of alum i.p. Some Hartley guinea pigs also received cyclophosphamide (250 mg/kg) before the first boost. English short-hair guinea pigs (previously shown to be good IgE producers) were immunized similarly but received no cyclophosphamide. Hartley animals receiving no cyclophosphamide inconsistently made low titered IgE anti-hapten antibody (1:100). Fifteen of 15 Hartley animals that received cyclophosphamide had high titers (1:2000) of IgE anti-hapten antibody. English short-hair animals had moderate titers (1:400), and not all animals responded. Thus, cyclophosphamide converted IgE nonresponder Hartley guinea pigs to uniformly high responders. This method provides material to study the biologic properties of IgE in this species, and also provides a model to study the apparent suppression of IgE responses in Hartley guinea pigs.