Background. The use of 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) may help to establish the antitumor activity of enzastaurin, a novel protein kinase C-beta II (PKC-betaII) inhibitor, in mouse xenografts. Methods. The hematologic cell line RAJI and the solid tumor cell line U87MG were each implanted in NOD/SCID mice. Standard tumor growth measurements and [(18)F]FDG PET imaging were performed weekly for up to three weeks after tumor implantation and growth. Results. Concomitant with caliper measurements, [(18)F]FDG PET imaging was performed to monitor glucose metabolism. Heterogeneity of glucose uptake in various areas of the tumors was observed after vehicle or enzastaurin treatment. This heterogeneity may limit the use of [(18)F]FDG PET imaging to measure enzastaurin-associated changes in xenograft tumors. Conclusion. [(18)F]FDG PET imaging technique does not correlate with standard caliper assessments in xenografts to assess the antitumor activity of enzastaurin. Future studies are needed to determine the use of [(18)F]FDG PET imaging in preclinical models.