Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease-specific mechanism involved in B-cell establishment within the central nervous system in MS.