Duloxetine hydrochloride is an antidepressant drug also approved for diabetic neuropathy, anxiety disorders, and fibromyalgia requiring repeated administration on chronic basis. The objective of this study was to develop a transdermal drug delivery system for duloxetine hydrochloride as a once daily dosage form. Transdermal patches were prepared by solvent evaporation method employing controlled release grades of HPMC in presence or absence of plasticizer PEG-400. FTIR and Differential scanning calorimetry ruled out drug polymer interactions. Standard procedures were used to analyze the prepared films for various physicochemical parameters, drug release (Franz diffusion cell) and skin irritation test. The formulations were uniform in their physical characteristics with low water vapor absorption, moisture loss and water vapor transmission implying excellent quality and uniformity in patch characteristics. The patches were devoid of hypersensitivity reactions on rat skin. The in-vitro and ex-vivo drug release studies for all the formulations showed that the first dose of the drug was released in 2.0-3.0 h and nearly complete release (94%) was achieved in 24 h. Transdermal patches were successfully prepared for duloxetine hydrochloride and their evaluation suggested excellent quality and uniformity in patch characteristics. This can have potential applications in therapeutic arena offering advantages in terms of reduced dosing frequency, improved patient compliance and bioavailability.