Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), which often produces Panton-Valentine leukocidin (PVL), is an emerging threat in the community. In Japan, for example, PVL-positive ST8 CA-MRSA (USA 300), which originated from the United States, persisted in families for a year and caused severe invasive infection in a child. In this study, we describe a long-term familial infection cluster caused by novel PVL-positive CA-MRSA, which most probably originated from India. This MRSA persisted in related families for more than 2 years with colonization of, for example, the nares and cheek. At least 6 of 12 members (50%) developed deep cutaneous abscesses, including recurrent and multifocal abscesses, every 1.2 months on average. All MRSA isolates from colonization and abscesses were the same, albeit with a variant in pulsed-field gel electrophoresis analysis. The MRSA exhibited the genotype ST22/spa113(t005)/SCCmecIVa/coagulase gene (coa) novel type and strong hemolysis activity. Moreover, the MRSA exhibited high biofilm formation (which was markedly enhanced by sub-MICs of oxacillin). Some patients were treated with levofloxacin, with successful MRSA eradication even from the whole body surface sites; however, short-term patient follow-up was not sufficient to demonstrate eradication of the familial infection cluster. The data suggest that PVL-positive novel ST22 CA-MRSA emerged in Japan, causing a long-term familial infection cluster, and that the success of ST22 CA-MRSA as both a colonizer and a pathogen could result from the combination of its strong biofilm formation and other virulence factors. A long-term patient (or carrier) follow-up is needed in the community.