Erythropoietin and iron has individually shown some beneficial effects on early-phase liver regeneration following partial hepatectomy (PHx); however, there are limited data on their combined effect on late-phase liver regeneration after PHx. Here we examined the combined effects of recombinant human erythropoietin (rhEPO, 3,000 IU/kg) and iron isomaltoside (IIM, 40 mg/kg) on late-phase liver regeneration following PHx and investigated the possible underlying mechanism. Rats administrated with rhEPO showed significantly higher liver mass restoration, interleukin-6 (IL-6, a hepatocyte mitogen) levels, and Ki-67-positive hepatocytes on day 7 after PHx than saline-treated controls. These beneficial effects were further enhanced on days 7 and 14 by co-treatment with IIM. This combination also significantly improved the liver function indices, such as increased the albumin production and decreased the bilirubin levels, but did not alter the serum levels of toxic parameters, such as aspartate transaminase and alanine transaminase. This study demonstrated that the combination of rhEPO and IIM synergistically improves the late-phase liver regeneration and function after PHx, probably by promoting IL-6-mediated hepatocyte proliferation without adverse effects. Therefore, this combination treatment can be considered as a potential therapeutic strategy for patients undergoing resection for hepatic malignancies.