The aim of this project was to study a mechanism that might explain the increased uptake of 18F-labeled FDG seen in inflammation. The approach chosen was to examine the effect on 18F-FDG uptake of acute activation of murine lymphocytes by concanavalin A (Con A). Methods: Immunocompetent BALB/c mice and nude mice received an intravenous injection of 10 mg/kg Con A. Twenty-four hours later, the mice received an intravenous injection of 0.74 MBq (20 μCi) 18F-FDG. One hour later, biodistribution was determined. The distribution of the radiolabel in the liver was also evaluated by autoradiography. In vitro 18F-FDG uptake to splenocytes from BALB/c mice with and without Con A pretreatment were determined 30, 60, and 120 min after the splenocytes were mixed with 18F-FDG (0.74 MBq [20 μCi]/200 μL). Results: In immunocompetent BALB/c mice, pretreatment with Con A significantly increased 18F-FDG uptake in the spleen and liver. Autoradiographs of the liver showed that pretreatment with Con A produced a specific localization of 18F-FDG at periportal areas, where numerous sites of cellular infiltration were observed. In vitro binding of 18F-FDG to the splenocytes was significantly higher for Con A-pretreated BALB/c mice than for control mice. Conclusion: This study showed that Con A increased 18F-FDG uptake. Con A-activated lymphocytes actively took up 18F-FDG both in vitro and in vivo, and 18F-FDG specifically accumulated in Con A-mediated acute inflammatory tissues.