Allergen-specific IgE plays a key role in the physiopathology of allergic disorders. This IgE response is usually accompanied by a production of IgG4. Indirect evidence suggests that IgG4 may not be a sensitizing Ab but, in contrast, could be protective. As such, it may be of potential therapeutic interest to selectively modulate IgE vs IgG4 production. To date, IgE and IgG4 switching seems to be controlled by common mechanisms. We report here that IL-10 has a differential effect on IgE vs IgG4 production by PBMC. IL-10 decreases ε transcript expression and IgE production induced by IL-4 when added during the first 3 days of in vitro culture, suggesting that IL-10 decreases IL-4-induced IgE switching. In contrast, if added later on B cells that are already IgE switched, IL-10 potentiates IgE production. Interestingly, whatever the time of addition, IL-10 augments IL-4-induced γ4 transcript expression and IgG4 production, with a maximal effect when added during the first 3 days. As IL-10 is not a switch factor for IgG4, it is likely that IL-10 enhances IgG4 production by potentiating IL-4-induced IgG4 switching. However, IL-10 may also act by enhancing the growth and/or differentiation of cells that are already IgG4 committed. Finally, CD40 ligation reverses the early down-regulating effect of IL-10 on IgE production. These results are the first evidence of a molecule that differentially regulates IgE vs IgG4 production, thereby suggesting the existence of a pathway (s) selectively controlling their production.