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Prostaglandin E(2) (PGE(2)) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of Slco2a1 deficiency on the body core temperature (Tc) and on the PGE(2) concentration in hypothalamus interstitial fluid (C(isf)) and CSF (C(csf)) of lipopolysaccharide (LPS; 100 μg/kg, i.p.)-treated mice of both sexes. Slco2a1(−/−) mice did not develop a febrile response. C(csf) was increased in Slco2a1(+/+) and Slco2a1(−/−) mice, and C(csf) of Slco2a1(−/−) mice was well maintained at 5 h after LPS injection (1160 pg/ml) compared with Slco2a1(+/+) mice (316 pg/ml). A microdialysis study revealed that C(isf) peaked at 2 h after LPS injection in Slco2a1(+/+) mice (841 pg/ml), whereas the increase in C(isf) was negligible in Slco2a1(−/−) mice. The PGE(2) plasma concentration in Slco2a1(−/−) mice (201 pg/ml) was significantly higher than that in Slco2a1(+/+) mice (54 pg/ml) at 1 h after LPS injection, whereas the two groups showed similar PGE(2) concentrations in the hypothalamus. Strong Oatp2a1 immunoreactivity was observed in F4/80-positive microglia and perivascular cells and in brain capillary endothelial cells. The changes in Tc and C(isf) seen in LPS-injected Slco2a1(+/+) mice were partially attenuated in monocyte-/macrophage-specific Slco2a1(−/−) (Slco2a1(Fl/Fl)/LysM(Cre/+)) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of C(isf), possibly by regulating PGE(2) secretion from F4/80-positive glial cells and/or facilitating PGE(2) transport across the blood–brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation. SIGNIFICANCE STATEMENT Fever is a physiological response caused by pyrogen-induced release of prostaglandin E(2) (PGE(2)) in the hypothalamus, which plays a central role in regulating the set-point of body temperature. However, it is unclear whether the prostaglandin transporter OATP2A1/SLCO2A1 is involved in this response. We show here that LPS-induced fever is associated with increased PGE(2) concentration in hypothalamus interstitial fluid (C(isf)), but not in CSF (C(csf)), by means of a microdialysis study in global Slco2a1-knock-out mice and monocyte-/macrophage-specific Slco2a1-knock-out mice. The results suggest that OATP2A1 serves as a regulator of C(isf) in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells and, therefore, may also play a role in PGE(2) transport across the blood–brain barrier.