This research project was to determine the extents of direct penetration across live rat skin from topical application of diclofenac and its ester prodrug. Diclofenac and its prodrugs were formulated into patches with different pressure sensitive adhesives. In vitro flux studies across the human epidermis and across hairless rat skin were conducted. Direct penetration across live rat skin from topical application of either a diclofenac acid patch or a glycerol diclofenac ester patch were evaluated with a dual agar gel in situ rat model. Diclofenac ester prodrugs showed higher in vitro fluxes from patches with polyisobutylene adhesives, while diclofenac acid showed higher fluxes in patches with polyacrylate adhesives. Direct penetration from diclofenac acid patch accounted for 0.12% of the drug absorbed into the body and 78% of the drug collected in the agar gel, and the numbers from glycerol diclofenac ester patch were 0.083% and 77%, respectively. Topical application of either diclofenac acid patch or its ester prodrug patch demonstrated some direct penetration across the live rat skin, but the extent of direct penetration across the live rat skin from the glycerol diclofenac ester patch was not advantageous over that from the diclofenac acid patch.