The current means of assessing response in prostate cancer are imprecise because changes in tumor size are often slow and difficult to document, and alterations in serum prostate-specific antigen (PSA) levels do not always correlate with clinical outcomes. Using the CWR22 human prostate cancer xenograft model, serial changes in prostate tumor metabolism were assessed after androgen withdrawal by [3H]deoxyglucose (DOG) accumulation in the tumors and noninvasively using positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose as a radiotracer. A significant decrease in [3H]DOG accumulation was observed at 48 h after androgen withdrawal [62% of preandrogen withdrawal value (95% confidence interval: 0.59, 0.65)], reaching a maximum decline at day 10 [38% of preandrogen withdrawal value (95% confidence interval: 0.37, 0.40)]. Using PET, parallel changes in tumor metabolism were demonstrated and preceded changes in tumor volume and marked declines in serum PSA. DOG accumulation returned to near baseline upon reintroduction of androgen. The decrease in DOG accumulation was associated with a decline in the proportion of tumor cells in active cell cycle from >60% to <5% at 7-10 days after androgen withdrawal. No increase in the proportion of tumor cells undergoing apoptosis was observed during this time period, implying an arrest in a G0/early G1 state. DOG accumulation in tumor cells, measured directly and by PET, correlated with androgen changes in the host. The results suggest that serial monitoring of DOG accumulation using PET scanning may be useful as an early indicator of treatment efficacy and other outcome measures in prostate cancer.