To determine the influence of high-efficacy disease modifying therapy (DMT) on the development of IgG SARS-CoV-2 antibody response in COVID-19 convalescent people with multiple sclerosis (pwMS). Seventy-four pwMS taking high-efficacy DMTs (specifically natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine and ublituximab) and diagnosed with COVID-19 and 44 healthy persons (HC) were enrolled. SARS-CoV2 antibodies were tested with Elecsys® Anti-SARSCoV-2 S assay. pwMS taking high-efficacy DMTs had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to healthy controls (33 negative pwMS 44.6% compared to one negative HC 2.3%, p < 0.001). pwMS taking B-cell depleting therapy (ocrelizumab and ublituximab) had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to pwMS on all other DMTs (29 negative pwMS on B-cell therapy 64.4% compared to four negative pwMS on all other DMTs 13.8%, p < 0.001). Out of other DMTs, two (33.3%) pwMS taking fingolimod and two (16.7%) pwMS taking cladribine failed to develop IgG SARS-COV-2 antibodies. B-cell depleting therapy independently predicted negative titer of IgG SARS-CoV-2 antibody (ExpB =0.014, 95%CI 0.002–0.110, p < 0.001). A significant proportion of convalescent COVID-19 pwMS on high-efficacy DMTs will not develop IgG SARS-CoV-2 antibodies. B-cell depleting therapies independently predict negative and low titer of IgG SARS-CoV-2 antibody. Display omitted •Convalescent COVID-19 people with multiple sclerosis (pwMS) taking high-efficacy DMTs had a significantly higher chance of negative titer of SARS-CoV2 antibodies compared to healthy controls.•pwMS taking B-cell depleting therapy had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to those on other high-efficacy DMTs.•B-cell depleting therapy was an independent predictor of negative and low titer of IgG SARS-CoV-2 antibody.