The identification of ricin toxin A‐chain (RTA) epitopes and the molecular context in which they are recognized will allow strategies to be devised that prevent/suppress an anti‐RTA immune response in patients treated with RTA‐based immunotoxins. RTA‐specific human T‐cell lines and T‐cell clones were produced by in vitro priming of PBMC. The T‐cell clones used a limited set of Vβ chains (Vβ1, Vβ2 and Vβ8) to recognize RTA epitopes. The use of RTA deletion mutants demonstrated that T‐cell lines and T‐cell clones from three out of four donors responded to RTA epitopes within the domain D124‐Q223, whereas one donor recognized the region I1‐D124. The response to RTA peptides of T‐cell lines and T‐cell clones from two donors allowed the identification of immunogenic segments (D124‐G140 and L161‐T190) recognized in the context of different HLA‐DRB1 alleles (HLA‐DRB1*0801, and HLA‐DRB1*11011 and B1*03011, respectively). The response to L161‐T190 was investigated in greater detail. We found that the HLA‐DRB1*03011 allele presents a minimal epitope represented by the sequence I175‐Y183 of RTA, whereas the HLA‐DRB1*11011 allele presents the minimal epitope M174‐I184. RTA peptides and an I175A RTA point mutant allowed us to identify I175 as a crucial residue for the epitope(s) recognized by the two HLA‐DRB1 alleles. Failure of T‐cell clones to recognize ribosome inactivating proteins (RIPs) showing sequences similar but not identical to RTA further confirmed the role of I175 as a key residue for the epitope recognized in the context of HLA‐DRB1*11011/03011 alleles.