Mutations of the p53 tumor suppressor gene are the most frequently observed genetic lesion in human cancer. Previously, we found that multiple intravenous injections of a liposome:p53 complex inhibited the growth of a malignant human breast cancer cell line that was implanted into nude mice. In the present study, we evaluated the toxicity of the liposome:p53 complex and the mechanism of this in vivo treatment in reducing tumor growth. Intravenously delivered liposome:p53 complex at dosages sufficient to inhibit human breast cancer in nude mice showed no evidence of toxicity. Clinical chemistries, complete blood counts, and histopathologic examination of various organs from the p53-treated groups did not demonstrate any difference from the control groups. To elucidate the mechanism by which the liposome:p53 complex inhibits cancer, the transfection efficiency of a liposome:chloramphenicol acetyltransferase (CAT) complex into the tumor was determined. Interestingly, less than 5% of the tumor was transfected with a liposome:CAT complex. A mechanism that could account for p53 reduction of tumor size and a low transfection efficiency is inhibition of angiogenesis. After one treatment, we found that the liposome:p53 complex reduced the number of blood vessels in the p53-treated group by approximately 60% compared to the control group (p < 0.001). The close correlation between the antitumor effect of p53 and the reduction of blood vessel density in the tumor suggests that p53 effects are mediated, at least in part, by an antiangiogenesis mechanism.