Significance The immunoglobulin heavy chain (IgH) 3′regulatory region ( 3′RR ) fine-tunes IgH gene expression during B cell development. One singularity of this region is its quasi-palindromic structure conserved in the 3′RR of other species. By comparing previous mouse knockout (KO) models ( 3′RR- and hs3b-4 KO) to a novel mutant devoid of the quasi-palindrome ( 3′PAL KO), we highlighted common features and differences that specify two distinct regulatory entities: ( i ) the distal module ( hs4 ) is sufficient for normal IgH expression up to the naïve B cell stage; ( ii ) during B-cell activation, the proximal module (quasi-palindrome) is important for both class switch recombination and somatic hypermutation; and ( iii ) in plasma cells, the quasi-palindrome is required for robust transcription of the IgH locus.