The combined repetitive oligopeptides (CROPs) of Clostridium difficile toxins A (TcdA) and B (TcdB) induce clathrin-mediated endocytosis of the toxins. Inconsistently, CROP-truncated TcdA(1-1874) is also capable of entering host cells and displaying full cytotoxic properties although with less potency. Pre-incubation of cells with isolated CROPs, however, reconstitutes the reduced uptake of TcdA(1-1874) to the level of the full-length toxin. We believe that TcdA exhibits an additional binding motif beyond the C-terminally located CROP domain, which might interact with cellular receptor structures that are associated with alternative internalization pathways. This study therefore evaluated endocytosis routes of CROP-dependent cellular uptake for TcdA and CROP-independent cellular uptake for TcdA(1-1874). Clathrin knockdown or inhibition with chlorpromazine affected subsequent internalization of TcdA and TcdA(1-1874), although only to some extent, arguing for alternative, clathrin-independent endocytosis routes. Inhibition of dynamin, a GTPase essentially involved in clathrin-mediated endocytosis as well as in various clathrin-independent uptake mechanisms, affected uptake of TcdA to the same extent as clathrin inhibition. In contrast, uptake of TcdA(1-1874) was almost completely eliminated in dynamin-inhibited cells. Thus, clathrin-independent uptake of TcdA(1-1874) presumably depends on dynamin. These findings demonstrate that the toxins are endocytosed via complex pathways involving clathrin and dynamin, putatively enabling them to adapt to mechanisms of various cell types. With regard to the emergence of C. difficile strains producing C-terminally truncated toxins, this study emphasizes the relevance of elucidating toxin uptake as a prerequisite for the development of toxin intervention strategies.