BACKGROUND: This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of (18)F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET). RESULTS: Tumor-bearing mice (squamous cell carcinoma) maintained at 37 degrees C were studied while breathing either normal air or carbogen (95% O(2), 5% CO2), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential (18)F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of (18)F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest (18)F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, (18)F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation. CONCLUSION: Tumor (18)F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance (18)F-FDG functional imaging.