It has previously been demonstrated in the setting of an isolated limb perfusion that application of high‐dose TNF‐α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low‐dose TNF‐α augments the antitumor activity of a liposomal formulation of doxorubicin (DOXIL®). Addition of TNF‐α to a DOXIL® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF‐α had been co‐administered. Administration of TNF‐α augmented DOXIL® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF‐α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome‐associated doxorubicin were not increased by TNF‐α. Therefore, we hypothesize that low‐dose TNF‐α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF‐α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley‐Liss, Inc.