It has been postulated that IL-2 secreting cancer vaccines establish antitumor immunity because the cytokine acting in a paracrine fashion would deliver a helper signal directly to the T cells making contact with the modified tumor cells at the site of vaccination. However, patterns of lymphocyte recirculation cannot be reconciled with the above direct interaction model: only primed memory T cells rather than naive T lymphocytes patrol the periphery, while naive T cells travel to the peripheral lymph nodes, where priming occurs. We have found that in vivo treatment of mice with the antibody MEL-14 directed against L-selectin, which is a molecule expressed at high levels on naive T cells, can completely abrogate protection against a mouse melanoma conferred by an IL-2 secreting vaccine. Since mouse memory CD4 and CD8 T cells are L-selectin-low, only migration of naive T cells is perturbed by the in vivo antibody blockade. Thus, priming of naive T cells in the draining lymph node is a critical step for the successful vaccination by IL-2 secreting cancer vaccines. Such priming is performed most efficiently by professional antigen presenting cells; consequently, these data also imply that allogeneic origin of tumor vaccines may not exclude successful vaccination.