The study was initiated with the aim of gaining insight into the existence of bacterial determinism for gastric extra-nodal marginal zone B-cell MALT lymphoma. DNA hydridization against the whole genome of 120 clinical isolates revealed a cluster of 19 H. pylori strains, all completely deprived of cagPAI sequences originating from patients with MALT lymphoma. We sequenced the genome of strain B38, a representative of this cluster, and describe the first genome sequence of a cagPAI minus H. pylori strain. The absence of the cagPAI, including that of several non-ubiquitous genes, makes the B38 genome the smallest H. pylori genome described to date. The cagPAI minus B38 strain lacks a functional cytotoxin (vacAs2m2) as well as genes encoding the major adhesion factors (absence of babB, babC, sabB, and homB); thus, compared with well-known pro-inflammatory H. pylori isolates, it appears to be deprived of all known pathogenic determinants, but is nonetheless associated with gastric neoplasia. Further investigation is required to fully understand the difference in fitness between these strains with low pro-inflammatory profiles and the human host factors that may play a significant role in the development of gastric MALT lymphoma.