Purpose: Intravenous access is difficult in some patients referred for 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor 18F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compare the human biodistribution and dosimetry of 18F-FDG for oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered 18F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous 18F-FDG dosimetry with older dosimetry data. Methods: Nine healthy volunteers (6 male and 3 female; ages 19-32 years) underwent PET combined with computed tomography (PET/CT) imaging after oral and intravenous administration of 18F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session 9 whole body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120 and 240 minutes (min) after 18F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time-activity curves. Time-integrated activity coefficients derived from time-activity curves were given as input to OLINDA/EXM for dose calculations. Results: Peak blood uptake following orally administered 18F-FDG was observed at 45-50 min after ingestion. The oral-to-intravenous ratios of 18F-FDG uptake for major organs at 45 min were: blood (1.07 ± 0.24), heart wall (0.94 ± 0.39), brain (0.47 ± 0.12), liver (1.25 ± 0.18) and kidneys (0.84 ± 0.24). The highest organ absorbed doses (µGy/MBq) for oral 18F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3) and brain (29.4 ± 5.1) and the effective dose was significantly higher (20%) than for intravenous administration (P = 0.002). Conclusion: FDG has excellent bioavailability following oral administration but peak organ activities occur later than post-intravenous injection. These data suggest PET at 2 h following oral 18F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h post-injection. Oral 18F-FDG is a palatable alternative to intravenous 18F-FDG when venous access is problematic. Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc.