Following the intrasplenic injection of B16F10 melanoma cells into mice, at first single cells, and later multicellular tumor foci were observed at different times in the liver. Cell numbers and tumor volumes were determined over the next 12 days, by confocal microscopy of thick liver sections. Fifteen minutes after injection, approximately 20% of the melanoma cells were identified in the liver microvasculature; after 48 hr, only 0.68% of these retained morphologic integrity; by 5 days only 0.13% of the originally detected cells incorporated BUdR; and, by 12 days, these subsequently grew into tumor nodules. Tumor volume changes with time were not exponential and, following a non‐replicative period during the first 2½ days, the volume doubling times increased from approximately 8 to 39 hr at 12 days. BUdR incorporation indicated that this was probably due to a diminishing proliferative fraction in the cancer‐cell population. When animals were killed at 12 days, tumor foci were centered on the liver sinusoids and appeared to represent expansive growth of arrested cells, with no evidence of parenchymal invasion by migrating cancer cells, in spite of the absence of a subendothelial basement membrane. Our direct observations indicate that, in this model system, the post‐delivery phase of hepatic colonization is characterized by high levels of inefficiency with respect to cancer‐cell survival, growth and extravasation. © 1992 Wiley‐Liss, Inc.