Purpose Blood glucose is routinely measured prior to 18F-fluorodeoxyglucose (FDG) administration in positron emission tomography (PET) imaging to identify hyperglycemia that may affect image quality. In this study we explore the effects of blood glucose levels upon semi-quantitative standardized uptake value (SUV) measurements of target organs and tissues of interest and in particular address the relationship of blood glucose to FDG accumulation in the brain and liver. Methods 436 FDG PET/CT consecutive studies performed for oncology staging in 229 patients (226 male) at the Ann Arbor Veterans Administration Healthcare System were reviewed. All patients had blood glucose measured (112.4 ± 34.1 mg/dL) prior to injection of 466.2 ± 51.8 MBq (12.6 ± 1.4 mCi) of FDG. SUV measurements of brain, aortic arch blood-pool, liver, and spleen were obtained at 64.5 ±10.2 min’ post-injection. Results We found a negative inverse relationship of brain SUV with increasing plasma glucose, levels for both absolute and normalized (either to blood-pool or liver) values. Higher blood glucose levels had a mild effect upon liver and blood-pool SUV. By contrast, spleen SUV was independent of blood glucose, but demonstrated the greatest variability (deviation on linear regression). In contrast to other tissues, liver and spleen SUV normalized to blood-pool SUV were not dependent upon blood glucose levels. Conclusion The effects of hyperglycemia upon FDG uptake in brain and liver, over a range of blood glucose values generally considered acceptable for clinical PET imaging, may have measurable effects on semi-quantitative image analysis.