Although passively administered antibodies are known to suppress the humoral immune response, the mechanism is not fully understood. Here, we developed a mathematical model to better understand the suppression phenomena in mice. Using this model, we tested the generally accepted but difficult to prove "epitope masking hypothesis." To simulate the hypothesis and clearly observe masking of epitopes, we modeled epitope-antibody and epitope-B-cell receptor interactions at the epitope level. To validate this model, we simulated the effect of the antibody affinity and quantity as well as the timing of administration on the suppression, and we compared the results with experimental observations reported in the literature. We then developed a simulation to determine whether the epitope-masking hypothesis alone can explain known immune suppression phenomena, especially the conflicting results on F(ab')2 fragment-induced suppression, which has been shown to be no suppression, or similar to or up to 1000-fold weaker than the suppression by intact antibody. We found that suppression was caused by a synergistic effect of both epitope masking and rapid antigen clearance. Although the latter hypothesis has lost support because FcgammaRI/III mutant mice show antibody-mediated suppression, our simulations predict that, even in FcgammaRI/III mutant mice, the immune response can be suppressed according to the antibody affinity. Our model also effectively reproduced the conflicting results obtained using F(ab')2 fragments. Thus, in contrast to the idea that the F(ab')2 results prove the FcgammaRIIb involvement in suppression, our mathematical model suggests that the epitope-masking hypothesis together with rapid antigen clearance explains the conflicting results.