The main purpose of this work was to develop biomedical electrospun nanofibrous mats based on a poly(vinyl alcohol)/poly(E >-caprolactone) (80/20) hybrid with a defined drug release rate using tetracycline hydrochloride as a model drug. The electrospinning process parameters, such as polymer solution concentration, distance between injecting syringe tip/collector, voltage, injected flow rate and the polyvinyl alcohol cross-linking time were optimized via a D-optimal design method for a suitable nanofiber diameter with an optimal drug release rate. The morphology of nanofibers and their mean diameters were studied by a scanning electron microscopy technique. The results showed that the mean diameters of nanofibers were significantly reduced after drug loading. The swelling, weight loss and biodegradability of nanofibers samples investigated by FTIR were also determined. Two main mechanisms via penetration and erosion were evaluated. In vitro drug release in a phosphate buffer environment at pH=7.2 for the samples demonstrated that the polymer type and hydrophilic nature of the polymer/drug system is very effective in the kinetics and mechanism of drug release. Hybridization of poly(vinyl alcohol)/poly(E >-caprolactone) with a known ratio showed to be a suitable and useful method in the electrospinning of nanofibers samples for superior control of the drug release rate. Finally, nanofibrous mats of polyvinyl alcohol and polyvinyl alcohol/poly(E >-caprolactone) hybrid (80/20) had much better drug release rate characteristics for tetracycline hydrochloride as a model drug compared with cast film samples loaded with the same drug.