We have analyzed the intracellular degradation of an immune complex after its FcgammaR-mediated uptake in antigen-presenting cells (APC). Mice that lack the cathepsins (Cat) S, L, B and D allowed us to assess the direct contribution of these individual proteases to the processing events observed. CatS and CatB mediate the bulk of degradation of the Ig-125I-labeled F(ab')2 immune complex delivered via FcgammaR, while CatL and CatD are dispensable. CatS and CatB are involved in independent processing pathways and can substitute in part for each other's absence. The combined ablation of both proteases reduces the rate of degradation observed by > 80 %. CatB is required for the generation of F(ab')23, a predominant degradation intermediate smaller by approximately 3 kDa than the 125I-labeled F(ab')2 itself. In addition, absence of CatB in vivo significantly affects the activity pattern of the remaining cysteine proteases. Thus, we conclude that CatB is a key enzyme for the proper degradation of an immune complex taken up by FcgammaR and for the control of protease activity in the endocytic pathway of APC.