Mutational heterogeneity represents one of the greatest barriers impeding the progress toward the clinic of gene therapies for many dominantly inherited disorders. A general strategy of gene suppression in conjunction with replacement has been proposed to overcome this mutational heterogeneity. In the current study, various aspects of this strategy are explored for a dominant form of the retinal degeneration, retinitis pigmentosa (RP), caused by mutations in the rhodopsin gene (RHO-adRP). While > 200 mutations have been identified in rhodopsin (RHO), in principle, suppression and replacement may be employed to provide a single mutation-independent therapeutic for this form of the disorder. In the study we demonstrate in a transgenic mouse simulating human RHO-adRP that RNA interference-based suppression, together with gene replacement utilizing the endogenous mouse gene as the replacement, provides significant benefit as evaluated by electroretinography (ERG). Moreover, this is mirrored histologically by preservation of photoreceptors. AAV-based vectors were utilized for in vivo delivery of the therapy to the target cell type, the photoreceptors. The results demonstrate that RNAi-based mutation-independent suppression and replacement can provide benefit for RHO-adRP and promote the therapeutic approach as potentially beneficial for other autosomal dominantly inherited disorders.