When considering drug delivery, the amount of drug that can be carried at a particular time and how the drug is incorporated efficiently into cells are important parameters. Transferrin (Tf)-conjugated nanocarriers have been used for the targeted delivery of drugs to cancer cells due to the availability of receptor-mediated clathrin-dependent endocytosis. In general, however, endocytosis seems to differ according to the size and shape of carriers. Large substances are generally internalized into cells by phagocytosis. We studied the internalization mechanism of Tf-conjugated nanoparticles (diameter, 522 nm). Tf-conjugated polystyrene particles were incorporated into cells by receptor-mediated endocytosis with large clathrin-coated vesicles even though their diameter was >500 nm and despite that fact that clathrin-coated vesicles have a diameter of ≈100 nm. This finding suggests that signals for internalization generated by stimulated Tf receptors (TfRs) activate clathrin-mediated endocytosis preferentially. Whether these larger particles could deliver drugs more efficiently than smaller particles was then examined. The toxicity of larger Tf-conjugated biodegradable nanoparticles (poly(lactic-co-glycolic acid)) encapsulating doxorubicin (diameter, 216 ± 38 nm) was appreciably dependent on the number of Tf molecules conjugated on a particle and the number of TfRs expressed on the cell membrane. Larger Tf-conjugated particles delivered drugs to cancer cells expressing many TfRs more selectively than their smaller counterparts (diameter, 56 ± 9 nm) if they were decorated with an appropriate number of Tf molecules.