Interstitial fluid pressure (IFP) is elevated in many experimental and human tumors, and high IFP is associated with poor prognosis in human cancer. The significance of elevated IFP in the development of metastatic disease was investigated in the present work by using A-07 human melanoma xenografts as models of cancer in humans. IFP was measured with the micropipette technique (tumor periphery) and the wick-in-needle technique (tumor center). Tumor hypoxia was studied by immunohistochemistry using pimonidazole as a hypoxia marker and by using a radiobiological assay. High central tumor IFP was found to be associated with the development of pulmonary (P = 0.000085) and lymph node (P = 0.000036) metastases in small (150-200 mm(3)) A-07 tumors. Hypoxic cells could not be detected in these tumors. Our study suggests that interstitial hypertension may facilitate tumor cell intravasation and, hence, promote metastasis by mechanisms independent of tumor hypoxia.