Abstract: A QSAR study has been performed on a series of substituted pyrido[3,2-b]pyrazinones as potent and selective PDE-5 Inhibitors. The compounds in the selected series were characterized by spatial, molecular and electrotopological descriptors using QSAR module of molecular design suite (V-Life MDS^TM 3.5). Correlations between inhibitory activities and calculated predictor variables were established through partial least square regression (stepwise forward) method. The generated QSAR models reveal that the topology of the molecules crucially influences the desired inhibitory activity of pyrido[3,2-b]pyrazinones. PDE-5 inhibition can be well defined by the models generated and the molecules are more selective towards PDE –5 while PDE –6 and PDE –11 inhibitory activities cannot be well delineated by the help of generated QSAR models. So PDE-5 selective compounds can be synthesized based on the assumption of the present QSAR analysis. The best model shows 90% correlation for PDE-5 inhibitory activity which explains good reliability of the model. However cross correlated regression coefficients (Q²) 0.5959 further validate the model significance. The present study imply that the PDE-5 inhibition can be augmented primarily by increasing molecular refractivity and number of carbons connected to the aromatic rings, single bonds and by decreasing number of carbons connected to the double bonds.