To examine the role of the early changes occurring in the liver within the first hours after a partial hepatectomy and in an attempt to demonstrate the involvement of subsequent regulatory mechanisms, the size of the remnant liver was modified at various times and by different surgical techniques. Male Wistar rats were submitted to a two-thirds "temporary partial hepatectomy" produced by a 3-h occlusion of the pedicle of the anterior lobes protected by local hypothermia. Various indexes of cell proliferation ([3H]thymidine uptake and 5-bromo-2'-deoxyuridine and proliferating cell nuclear antigen labeling) were not increased despite a c-myc expression as high as that observed after a two-thirds partial hepatectomy. The temporary partial hepatectomy and a sham operation induced modifications of the hepatocytes, allowing rapid DNA synthesis after a subsequent two-thirds partial hepatectomy. After this initial nonspecific response, the extent of the regenerative response is determined according to the size of the liver mass present approximately from the 10th to the 18th hour after the initial stimulus. For instance, when a one-third partial hepatectomy was converted into a two-thirds partial hepatectomy at the 10th hour, the DNA synthesis at the 24th hour reached the value observed after a straightforward two-thirds partial hepatectomy. Inversely, the regenerative response was significantly reduced when additional liver lobes were connected to neck vessels between the 14th and the 18th hour after a two-thirds partial hepatectomy. In conclusion, the actual liver mass present during the period corresponding to mid- to late G1 appears to control the magnitude of the proliferative response, which is not the simple consequence of the early changes following a partial hepatectomy.