Gene transfer to exocrine glands, including the major salivary glands, presents an attractive method to deliver proteins for therapeutic applications. Previous efforts using nonviral gene delivery to these glands have resulted in limited success. In this report, zinc and other divalent transitions were coadministered with plasmid DNA in an effort to improve nonviral salivary gland transfection efficiency. The inclusion of zinc into plasmid DNA solutions resulted in a 20-fold enhancement in transgene expression without noticeable inflammation compared to a solution of plasmid DNA only. This observed enhancement in transgene expression was dependent upon the DNA dose and correlated with the accumulation of plasmid DNA by salivary gland tissues.