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We recently reported that multiple sclerosis (MS) plasma contains IgG aggregates and induces complement-dependent neuronal cytotoxicity (Zhou et al., 2023). Using ELISA, we report herein that plasma IgG levels in the aggregates can be used as biomarkers for MS. We enriched the IgG aggregates from samples of two cohorts (190 MS and 160 controls) by collecting flow-through after plasma binding to Protein A followed by detection of IgG subclass. We show that there are significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS IgG aggregates, with an AUC >90%; higher levels of IgG1 distinguish secondary progressive MS from relapsing-remitting MS (AUC = 91%). Significantly, we provided the biological rationale for MS plasma IgG biomarkers by demonstrating the strong correlation between IgG antibodies and IgG aggregate-induced neuronal cytotoxicity. These non-invasive, simple IgG-based blood ELISA assays can be adapted into clinical practice for diagnosing MS and SPMS and monitoring treatment responses. • Enriched the IgG aggregates by collecting flow-through after plasma binding to Protein A (A-FT). • Significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS plasma A-FT. • Higher plasma IgG1 can distinguish secondary progressive MS (SPMS) from relapsing-remitting MS (RRMS). • Strong correlation between IgG antibodies and IgG-induced neuronal cytotoxicity. • Provided evidence for a noninvasive blood-based IgG biomarker for MS. [ABSTRACT FROM AUTHOR]