The fate of bloodborne malignant melanoma cells selected for their enhanced ability to form lung colonies was examined to determine how specific tumor cells are arrested in certain organs during the experimental metastasis process. After murine B16 melanoma variant tumor cell lines with low (B16-F1) or high (B16-F10) survival and growth potential in vivo were admisistered by iv or intracardiac injections into syngeneic C57BL/6 mice, the quantitative distribution of [125l]5-iodo-2'-deoxyuridine (125IUDR)-labeled cells in the organs and subsequent formation of metastatic lung colonies were assessed. The initial distribution of viable tumor cells was dependent on the route of injection: Soon after iv injection, more 125IUDR-labeled B16 cells were localized in the lungs and fewer in the blood and other organs than after intracardiac injection. However, 1 day after the injection, the number of viable tumor cells in the lungs was independent of the route of injection, and at 14 days the quantity of resulting lung tumor colonies was similar. Variant line B16-F10 cells were better arrested and formed more tumors per input cell than B16-F1, regardless of the injection route. B16-F10 yielded only lung tumor colonies, whereas B16-F1 formed some extrapulmonary tumor growths. The results suggested that the ultimate fate of circulating tumor cells was not determined solely by nonspecific arrest in the capillary bed of the first organ encountered, and that in vivo selection could produce tumor line variants with organs preferences.