This study aims to evaluate the in vivo and in vitro performance of simple, cost effective and conventional single layer matrix tablet compared to pellets based on pelletization technology. Venlafaxine and its active metabolite ortho desmethyl venlafaxine is an antidepressant. Extended release tablets of Venlafaxine hydrochloride to be taken once daily were formulated with Venlafaxine hydrochloride equivalent to 150 mg of base. Matrix system based on swellable polymer Hydroxypropyl methylcellulose was selected for extending the drug release. The optimized formulation was subjected to stability studies at accelerated condition. Test and marketed formulations were evaluated for appearance, weight variation, thickness, hardness, friability, drug content and in vitro drug release. In vivo studies were carried out for the optimized formulation in 12 healthy human volunteers and pharmacokinetic parameters were compared with the marketed one. © 2012 Elsevier B.V., All rights reserved.