Malignant tumors frequently show an organ-specific metastatic spread, the causes of which are still largely unknown. Using an experimental tumor model, a methylcholanthrene-induced pleomorphic myofibrosarcoma ER 15-P of the C57Bl6J mouse, we wanted to find out whether this phenomenon is due to an adaptation or to a selection of tumor cells. After i.v. injection of tumor cells from the primary ER 15-P into the tail vein of male mice, metastases were regularly found in the lungs, mediastinal lymph nodes, and brain, as well as in the liver and kidneys, and occasionally in the adrenals. The following experimental procedures were used to isolate a tumor cell line with a possible liver preference: (1) Tumor cells from the primary ER 15-P were injected into a mesenteric vein of male mice. Tumor cells from the resulting liver colonies were again injected into the portal system of one group of mice. In a second group, part of the same cell suspension was injected into the tail vein. This procedure was performed four times. (2) Tumor cells from the primary ER 15-P were applied into the tail vein of male mice. Tumor cells from the resulting liver metastases were reinjected directly into the tail vein. This experiment was repeated three times. (3) Tumor cells from the primary ER 15-P were injected into the tail vein of male mice. Tumor cells from liver metastases were then injected, first, into the portal system of one group of male mice, and thereafter into the tail vein of another group of animals. This experiment was repeated twice. The following results were obtained: (1) By a repeated adaptation of tumor cells from the primary ER 15-P to liver tissue, no tumor cell line could be isolated that would show a preferential metastatic spread to this organ after tail-vein injection. (2) Repeated i.v. passages of tumor cells from liver metastases into the tail vein led to the selection of a tumor cell line with a tendency to liver metastasis. (3) Tumor cells selected from liver metastases induced via tail-vein injection showed, after a prolonged stay in the liver and a successive i.v. passage into the tail vein, a marked specificity for this organ. These results indicate that the liver-specific spread of tumor cells in our model is based on the selection of a tumor cell line from the primary ER 15-P influenced by the hepatic microenvironment.