Gene transfer to retinal cells may provide a means to retard photoreceptor cell death and thus prevent blindness in diseases such as retinitis pigmentosa. We tested the possibility of interfering with apoptotic photoreceptor cell death in rd mouse through subretinal delivery of a recombinant replication-defective adenovirus containing the human cDNA for bcl-2, Ad.2.5HRPbcl-2. Photoreceptor-specific transgene expression was accomplished through incorporation of the 2.5 kb human rhodospin upstream fragment (HRP). Ad.2.5HRPbcl-2 was injected alone or in combination with Ad.CMVPDEβ. Ad.CMVPDEβ contains a cDNA encoding the beta subunit of cGMP phosphodiesterase (PDEβ). Recombinant viruses containing lacZ (driven either by the cytomegalovirus (CMV) promoter/enhancer or HRP) and of Ad.CMVPDEβ and vehicle alone were injected in contralateral eyes as control. Injection of Ad.2.5HRPbcl-2 in the rd mouse resulted in histologically detectable rescue lasting 6 weeks after birth. Extent of rescue was not as large as after delivery of wild-type PDEβ, the gene defective in the rd mouse. However, delivery of genes which prevent apoptotic cell death may have broad application to gene therapy of retinal degenerative diseases.