Many multiple sclerosis (MS) patients treated with IFNbeta develop anti-IFNbeta antibodies, which can interfere with the bioactivity of the injected cytokine, i.e., antibody-mediated decreased bioactivity (ADB). The precise levels of anti-IFNbeta antibodies inducing decreased bioactivity is unknown. We repeatedly used a bioactivity measure, gene expression of MxA or GEM, and correlated bioactivity with measures of binding and neutralizing antibodies. The binding antibody assay was a capture ELISA, and the neutralizing antibody (NAb) assay was a cytopathic effect (CPE) assay. 27% (17/64) of patients repeatedly sampled developed critical ADB. Bioactivity as determined by GEM correlated negatively with NAb titer, and bioactivity that had been lost with the development of NAbs returned if NAb levels diminished. These data reveal that the GEM assay is a useful adjunct in the management of MS patients treated with IFNbeta, and that lost bioactivity returns when anti-IFNbeta antibody levels diminish.