Laminin (LN) α2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LNα1 chain in mice can compensate for the absence of LNα2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LNα1 chain transgene in skeletal muscle of LNα2 chain deficient mice. LNα1 is not normally expressed in muscle, but the transgenically produced LNα1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains (α4, β2). In 4-month-old mice, LNα1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LNα1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LNα2 chain deficiency by LNα1 chain may serve as a paradigm for gene therapy of CMD in patients.