Multiple sclerosis (MS) cerebrospinal fluid and brain contain increased IgG and oligoclonal bands. Whether this oligoclonal and polyclonal IgG is directed against a disease‐relevant antigen remains unknown. To distinguish between random activation versus a targeted B‐cell response, we analyzed the IgG heavy chain variable region (V_H) repertoire expressed in different lesions of an acute MS brain. To obtain a representative sample of the V_H repertoire, we constructed directional complementary DNA libraries from plaque‐periplaque messenger RNA and amplified V_H regions from the library by nested polymerase chain reaction. When MS V_H sequences were aligned to germline segments, about 60% of different V_H sequences in the acute MS brain were V_H4 germline segments, significantly greater than the known approximately 20% V_H4 germline prevalence. Specific V_H sequences were overrepresented and expressed at multiple plaque sites. Within some overexpressed populations, there were distinct sequence differences (clonal variants) indicative of clonal expansion. Alignment of V_H sequences to their closest germline counterparts revealed extensive somatic mutation and the preferential accumulation of amino acid replacement mutations in complementarity determining regions. These observations suggest the limited B‐cell response found in this acute MS brain was antigen driven.