Topical formulations of non-steroidal anti-inflammatory drugs are often used to provide effective local drug concentration while limiting systemic exposure and associated adverse events. Formulation composition has great influence on the rate of transdermal drug transport through human skin. This study was performed to compare the ex vivo transdermal transport of diclofenac from three topical formulations, a 1% liposomal gel formulation of diclofenac sodium and two emulsion gel formulations, 1.16% and 2.32% diclofenac diethylamine (equivalent to 1% and 2% diclofenac sodium). Human skin was obtained during unrelated surgical procedures and frozen at -20 °C until use. Three skin specimens were thawed, prepared for testing, and placed in a Franz cell with the stratum corneum facing the donor compartment. About 200 μl of each formulation was placed on the skin, and the receptor compartment fluid (phosphate buffered saline, pH 7.4, 32 °C) was sampled over the next 48 h. Diclofenac concentration was measured with a validated HPLC method. The transdermal permeability coefficient for the liposome 1% gel was 69.3 ± 14.4 10⁻⁸ cm•s⁻¹, compared with 34.9 ± 9.1 10⁻⁸ cm•s⁻¹ (P = 0.001) and 47.1±9.5 10⁻⁸ cm•s⁻¹ (P = 0.005) for the emulsion gel 1.16% and emulsion gel 2.32%, respectively. A statistically significant difference between transdermal transport of diclofenac from the liposome gel 1% and the emulsion gel 1.16% was evident after 9 h, a clinically relevant result because these products are typically applied 2 to 4 times daily. Based on these observations, liposome gel 1% formulation of diclofenac may have a clinical advantage compared with the emulsion gel 1.16% formulation.