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BACKGROUND Lactoferrin (LF) is a member of the transferrin family which is known for its immuno-modulatory properties. LF has been widely used as an anticancer medication in various cancers including breast cancer. AIMS The current study aimed to examine the molecular mechanisms underlying the therapeutic potential of recombinant human lactoferrin (rhLF), either alone or combined with epirubicin (EPI), in mice bearing solid Ehrlich carcinoma (SEC). METHODS SEC-bearing female mice (n=40) were divided into 4 equal groups. Mice were given rhLF orally (100 mg/kg/mouse) daily and/or EPI i.p (8 mg/kg/mouse). The experiment lasted for 14 days after which the samples were collected for measuring IL-18 and phosphorylated c-Jun N-terminal kinase (p-JNK) by ELISA and p53 gene expression by real time PCR. RESULTS Administration of rhLF, either alone or combined with EPI, markedly decreased the tumor volume and increased tumor inhibition rate as well as survival rate compared to either tumor control group or EPI-monotreated group. Also, co-administration of rhLF and EPI increased the level of activated JNKs and expression of p53 in tumor tissues compared to the tumor control group, exhibiting their pro-apoptotic properties. Moreover, the combined treatment with rhLF and EPI elevated IL-18 level in the intestinal mucosa compared to other experimental groups with a possible immune-enhancing effect. CONCLUSION Recombinant human lactoferrin exhibited potential anticancer and immuno-enhancing properties in mice with breast cancer. Co-treatment with rhLF and EPI proved to be a promising strategy in cancer treatment.