The association of human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) has been supported by several immunological and molecular studies. Recently, membrane cofactor protein (CD46) has been identified as the cellular receptor for the A and B variants of HHV-6. Elevated levels of soluble CD46 (sCD46) have been reported in the serum and CSF of MS patients. The aim of this study was to investigate a possible correlation between elevated levels of soluble CD46 and the presence of serum HHV-6 DNA in MS patients. An immunoaffinity column comprised of immobilized monoclonal antibodies to CD46 was developed to isolate sCD46 from cell free body fluids of MS patients and controls. After immunoaffinity purification, DNA was extracted from anti-CD46 column eluates and subjected to PCR amplification. Of the 42 MS samples tested, 4 serum samples were HHV-6 positive, 3 of which were typed as HHV-6A. The co-purification of sCD46 and HHV-6 DNA from MS sera indicates that HHV-6 is tightly connected to its receptor, CD46, in the serum of MS patients.