The failure to eliminate self‐reactive T cells during negative selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T‐cell receptors (TCRs) may form unstable complexes with self‐peptide–MHC by adopting suboptimal binding topologies compared with anti‐microbial TCRs. Alternatively, escape can occur by weak binding between self‐peptides and MHC. We determined the structure of a human autoimmune TCR (MS2‐3C8) bound to a self‐peptide from myelin basic protein (MBP) and the multiple sclerosis‐associated MHC molecule HLA‐DR4. MBP is loosely accommodated in the HLA‐DR4‐binding groove, accounting for its low affinity. Conversely, MS2‐3C8 binds MBP–DR4 as tightly as the most avid anti‐microbial TCRs. MS2‐3C8 engages self‐antigen via a docking mode that resembles the optimal topology of anti‐foreign TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3β conformation, this docking mode compensates for the weak binding of MBP to HLA‐DR4 by maximizing interactions between MS2‐3C8 and MBP. Thus, the MS2‐3C8–MBP–DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity.