Several studies have shown a decrease in blood perfusion and oxygen partial pressure (pO2), 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 pO2 were measured in nine human tumor xenografts in immunodeficient mice at a fixed tumor size (approximately 250 mm3). IFP and pO2 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 < .07); however, median pO2 decreased from approximately 35 mm Hg in 100-mm3 tumors to approximately 15 mm Hg in tumors of approximately 500 mm3 (P < 0.001). In HGL-9 tumors an inverse correlation between IFP and pO2 was found; IFP increased (P < 0.001) and pO2 decreased (P < 0.001) with increasing tumor size. At a fixed tumor size of 250 mm3 no correlation was found between mean IFP and median pO2 (P < 0.5) or between the mean IFP and the hypoxic fraction (pO2 < 2.5 mm Hg) (P < 0.7) in the nine tumors studied. The absence of a general relationship between IFP and pO2 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.(ABSTRACT TRUNCATED AT 250 WORDS)