Significance Many forms of muscular dystrophy produce muscle weakness through injury to skeletal muscle myofibers and specifically disruption of the muscle plasma membrane. Using a mouse model of muscular dystrophy in a genetically diverse background, a genome-wide scan for genetic modifiers was undertaken. A modifier locus that altered plasma membrane leak was interrogated, and a splice site variant in Anxa6, encoding annexin A6, was identified. The Anxa6 splice site produces a truncated annexin A6 protein. The truncated annexin A6 protein was found to inhibit membrane repair by disrupting the formation of the normal annexin A6-rich cap and repair zone. These data demonstrate annexin A6's role in muscle membrane leak and repair in muscular dystrophy.