PURPOSE: Small animal imaging is of growing importance for preclinical research and drug development. Tumour xenografts implanted in mice can be visualized with a clinical PET/CT (cPET); however, it is unclear whether early treatment effects can be monitored. Thus, we investigated the accuracy of a cPET versus a preclinical muPET using (18)F-FDG for assessing early treatment effects. MATERIALS AND METHODS: The spatial resolution and the quantitative accuracy of a clinical and preclinical PET were evaluated in phantom experiments. To investigate the sensitivity for assessing treatment response, A431 tumour xenografts were implanted in nude mice. Glucose metabolism was measured in untreated controls and in two therapy groups (either one or four days of antiangiogenic treatment). Data was validated by gamma-counting of explanted tissues. RESULTS: In phantom experiments, cPET enabled reliable separation of boreholes>/=5mm whereas muPET visualized boreholes>/=2mm. In animal studies, muPET provided significantly higher tumour-to-muscle ratios for untreated control tumours than cPET (3.41+/-0.87 vs. 1.60+/-.0.28, respectively; p<0.01). During treatment, cPET detected significant therapy effects at day 4 (p<0.05) whereas muPET revealed highly significant therapy effects even at day one (p<0.01). Correspondingly, gamma-counting of explanted tumours indicated significant therapy effects at day one and highly significant treatment response at day 4. Correlation with gamma-counting was good for cPET (r=0.74; p<0.01) and excellent for muPET (r=0.85; p<0.01). CONCLUSION: Clinical PET is suited to investigate tumour xenografts>/=5mm at an advanced time-point of treatment. For imaging smaller tumours or for the sensitive assessment of very early therapy effects, muPET should be preferred.