The objective of this work was to develop a simple and inexpensive transdermal formulation containing Nortriptyline Hydrochloride (NTH) for smoking cessation support therapy. Hydroxypropyl-methyl-cellulose was chosen as polymer and a mixture of transdermal enhancers (selected from previous research) was incorporated. The formulations were characterised in terms of appearance, thickness, uniformity of NTH content, release and skin permeation. Release studies demonstrated controlled release for four formulations. Diffusion studies were performed through human heat separated epidermis (HHSE) using Franz Diffusion Cells (FDC). Patches provided different fluxes varying from 20.39+/-7.09 microg/(cm(2) h) to 256.19+/-94.62 microg/(cm(2) h). The penetration profiles of NTH within the stratum corneum (SC) and deeper skin layers (DSL) were established after three administration periods (3 h, 6 h, and 24 h). Skin changes induced by the application of the patches were observed by confocal laser scanning microscopy (CLSM). The highest flux obtained would provide the recommended doses for smoke cessation support therapy (25-75 mg per day) with a 2 cm x 2 cm patch or a 3.5 cm x 3.5 cm patch, respectively, without skin damage evidence.