Inactivated SIV vaccines provide potent protection against challenge by SIV in the macaque model. Following evidence that host cell antigens can confer protection, and evidence that this protection can be conveyed to naive macaques in serum transfer experiments, we now show that this protection is due to immunity against HLA class II proteins. Recently it was shown that humans immunised with inactivated virus made an antibody response against HLA class I and II antigens expressed on the surface of the cell line used to grow the virus. Importantly, immunised individuals did not break tolerance to self-antigens. Here we show protection via different epitopes on the HLA class II protein in xeno-immunised macaques that may provide a correlate of protection.