Helicobacter pylori, Gram‐negative, curved bacteria colonizing the human stomach, possess strain‐specific complements of functional restriction–modification (R–M) systems. Restriction–modification systems have been identified in most bacterial species studied and are believed to have evolved to protect the host genome from invasion by foreign DNA. The large number of R–Ms homologous to those in other bacterial species and their strain‐specificity suggest that H. pylori may have horizontally acquired these genes. A type IIs restriction–modification system, hpyIIRM, was active in two out of the six H. pylori strains studied. We demonstrate now that in most strains lacking M.HpyII function, there is complete absence of the R–M system. Direct DNA repeats of 80 bp flanking the hpyIIRM system allow its deletion, resulting in an ‘empty‐site’ genotype. We show that strains possessing this empty‐site genotype and strains with a full but inactive hpyIIRM can reacquire the hpyIIRM cassette and functional activity through natural transformation by DNA from the parental R–M⁺ strain. Identical isolates divergent for the presence of an active HpyII R–M pose different restriction barriers to transformation by foreign DNA. That H. pylori can lose HpyII R–M function through deletion or mutation, and can horizontally reacquire the hpyIIRM cassette, is, in composite, a novel mechanism for R–M regulation, supporting the general hypothesis that H. pylori populations use mutation and transformation to regulate gene function.