The aim of this study was the production of ondansetron hydrochloride loaded polymeric microspheres for delivery via the nasal route with aim to avoid hepatic first-pass metabolism, and enhance residence time. The microspheres were prepared by the spray-drying technique using pectin as the polymer. The objective of this study was to examine extensively the influence of formulation and process variables on the characteristics of the microspheres prepared. The effects of various experimental parameters such as drug to polymer concentration and liquid feed flow rate on particle size and entrapment efficiency were evaluated by means of experimental factorial designs. A 3(2) full factorial design was employed in formulating the microspheres with polymer concentration (X-1) and liquid feed flow rate (X-2) as independent variables and particle size and entrapment efficiency were dependent variables. The results showed that the X1X2 interaction had effect on particle size where as X-2 alone effect on entrapment efficiency. The optimal microspheres were evaluated with respect to zeta potential study, drug release kinetic study, ex vivo permeation study, histological examination, stability study and in vivo study. Microspheres were characterized by differential scanning calorimetry, scanning electron microscopy and X-ray diffraction study. Scanning electron microscopy confirmed the smooth spherical surface of microspheres where as kinetic model revealed that drug release followed case II transport. The nasal delivery showed increased bioavailability as compared to oral delivery. In conclusion, the pectin containing microspheres of ondansetron hydrochloride with mucoadhesive property are suitable for nasal delivery. (C) 2012 Elsevier B.V. All rights reserved.