Systemic antigen-induced PCs are generated in inductive lymphoid tissues. Some of them are selected to travel through the circulation and finally, to home onto BM niches. BM PCs show prolonged survival and secrete high-affinity antibodies. In this study, human PCs were isolated from tonsil, blood, and BM, their IGHV3 and IGHV6 genes were sequenced, and their SHM were evaluated. The SHM analysis reveals the existence of a maturational gradient in these genes, as demonstrated by a progressive increase in the frequency of total and R mutations and total and NC aa changes following the direction: tonsil --> blood --> BM. The ratio of R to S mutations in the CDR1 and -2, but not in the FRs, increases from tonsil to blood and BM; this parameter reaches a maximum threshold when more than 10 mutations/sequence occur. Further analyses indicate that CDR1 and CDR2 SHM followed different strategies to provide appropriate amino acid changes, but both exhibited maximal resistance to incorporating drastic molecular alterations in the BM PCs. Finally, all of the findings are similar in IGHV3 and IGHV6 sequences, indicating that they reflect general rules imposed by in vivo antigen selection.