There has been intense interest in treating neurodegenerative conditions by passive immunotherapy. Here we describe the treatment of mice infected intraperitoneally (ip) with 104.6 infectious units of Rocky Mountain Laboratory (RML) prions, with bi-weekly injections of ip anti-prion monoclonal antibodies (mAbs). Mab ICSM18 (prion protein (PrP) epitope 143-153) raised to recombinant PrP, and ICSM35 (prion protein epitope 93-105) raised to an alternatively folded form of PrP, were both used at doses of 1 mg/week, or 0.25 mg/week. Treatment was given when prion infection was well established, 30 days after inoculation. Treatment resulted in a reduction in disease-related PrP (PrPSc) in the spleen and a significant extension in survival with both mAbs. ICSM18 showed a dose response and was more potent than ICSM35 with a 40% survival at 300 days postinfection using a dose of 1 mg/week. mAb treatment did not disrupt the normal function of the immune system. We have successfully demonstrated that the course of RML prion infection in mice can be safely attenuated by the early treatment with anti-PrP mAbs, at lower doses than previously reported. Humanised versions of these two mAbs will undergo safety-testing prior to manufacture for first-in-man study.