3D OSAR studies using CoMFA and CoMSIA have been carried out using 40 antihistamines H1 belonging to substituted benzyl piperazines/piperidines, pyrazinopyridoindoles, pyrazinoisoquinolines and semirigid analogs of diphenhydramine. Chemical feature based pharmacophoric alignments were used to develop models using different fields viz. tripos standard, hydrogen bonding, parabolic indicator in the case of CoMFA and steric, electrostatic, donor, acceptor, hydrophobic, donor and acceptor, steric and electrostatic in the case of CoMSIA. All the eleven derived models were further optimized using the PLS region focusing tool to increase the model resolution which led to eleven more models. The removal of two outliers led to statistically significant models. The best CoMFA model was the one developed using the (region focused) CoMFA parabolic fields $(r^2=0.988,q^2)_{ ext{LOO}} = 0.596, q^2$ Leave 10% out =0.592, $q^2$ Leave 30% out = 0.606) and the best CoMSIA model was the one with (region focused) CoMSIA steric fields (r2=0.989, $q^2$ Loo =0.74, $q^2$ Leave 10% out = 0.726, $q^2$ Leave 30% out $=0.74$ ).