Fever is associated with increased survival during acute infection, although its mechanism of action is largely unknown. This study found evidence of an unexpectedly integrated mechanism by which fever-range temperatures stimulate lymphocyte homing to secondary lymphoid tissues by increasing L-selectin and α4β7 integrin–dependent adhesive interactions between circulating lymphocytes and specialized high endothelial venules (HEV). Exposure of splenic lymphocytes in vivo to fever-like whole-body hyperthermia (WBH; 39.8 ± 0.2°C for 6 hours) stimulated both L-selectin and α4β7 integrin–dependent adhesion of lymphocytes to HEV under shear conditions in lymph nodes and Peyer patches. The adhesiveness of HEV ligands for L-selectin and α4β7 integrin (ie, peripheral lymph node addressin and mucosal addressin cell adhesion molecule-1) also increased during WBH or febrile responses associated with lipopolysaccharide-induced or turpentine-induced inflammation. Similar increases in HEV adhesion occurred during hyperthermia treatment of lymph node and Peyer patch organ cultures in vitro, indicating that the local lymphoid tissue microenvironment is sufficient for the hyperthermia response. In contrast, WBH did not augment adhesion in squamous endothelium of nonlymphoid tissues. Analysis of homing of α4β7^hi L-selectin^lo murine TK1 cells and L-selectin^hi α4β7 integrin-negative 300.19/L-selectin transfectant cells showed that fever-range temperatures caused a 3- to 4-fold increase in L-selectin and α4β7 integrin–dependent trafficking to secondary lymphoid tissues. Thus, enhanced lymphocyte delivery to HEV by febrile temperatures through bimodal regulation of lymphocyte and endothelial adhesion provides a novel mechanism to promote immune surveillance.