Malignant gliomas remain incurable entities that provide fertile ground for experimental therapy. The observation that impaired p53 expression is present in a proportion of these tumors suggests that reconstitution of this ability may impart some degree of tumor control. In this investigation, the 9L and RG2 intracranial rodent tumor models are utilized to assess SCH58500, an adenoviral p53 delivery system. The RG2 tumors demonstrate a greater propensity for transfection with this vector in vitro than the 9L tumors. In vivo, little tumor transfection beyond the immediate area of the needle tract used for direct SCH58500 injection was observed in either tumor type. Intracarotid injection resulted in no tumor transfection. Even at high concentrations of SCH58500 or control virus, injections resulted in no apparent toxicity in terms of weight gain, eating habits or activity in normal animals. The intratumoral administration of SCH58500 enhances the survival of animals with established 9L tumors. Both SCH58500 and its control viral construct not containing the p53 gene enhance survival in animals with RG2 tumors. None of the injected viral constructs caused an alteration in the markers used to detect the character of the white cell infiltrate in either of these tumors. Utilization of SCH58500 provides measurable efficacy in these preclinical brain tumor models without significant toxicity.