Several studies have shown a decrease in blood perfusion and oxygen partial pressure (pO 2), and an increase in interstitial fluid pressure (IFP) with increasing tumor size. However, it is not evident if the elevated IFP is a key parameter responsible for the poor perfusion and oxygenation of solid tumors. To this end, IFP and pO 2 were measured in nine human tumor xenografts in immunodeficient mice at a fixed tumor size (∼250 mm 3). IFP and pO 2 were also measured as a function of tumor volume in one human colon adenocarcinoma (LS174T) and in one human glioblastoma (HGL-9). In LS174T tumors IFP did not vary with size ( P < 0.7); however, median pO 2 decreased from ∼35 mm Hg in 100-mm 3 tumors to ∼15 mm Hg in tumors of ∼500 mm 3 ( P < 13.001). In HGL-9 tumors an inverse correlation between IFP and pO 2 was found; IFP increased ( P < 0.001) and pO 2 decreased ( P < 0.001) with increasing tumor size. At a fixed tumor size of 250 mm 3 no correlation was found between mean IFP and median pO 2 ( P < 0.5) or between the mean IFP and the hypoxic fraction (pO 2 < 2.5 mm Hg) ( P < 0.7) in the nine tumors studied. The absence of a general relationship between IFP and pO 2 could result in part from differences in vascular resistance between tumors. For example, a high geometric resistance to blood flow on the arterial side will lead to a low IFP and blood flow, whereas an elevation of the venous resistance will reduce blood flow and increase IFP. In conclusion, our results show that there is no general relationship between IFP and oxygen levels in solid tumors.