We present TrixP, a new index-based method for fast protein binding site comparison and function prediction. TrixP determines binding site similarities based on the comparison of descriptors that encode pharmacophoric and spatial features. Therefore, it adopts the efficient core components of TrixX, a structure-based virtual screening technology for large compound libraries. TrixP expands this technology by new components in order to allow a screening of protein libraries. TrixP accounts for the inherent flexibility of proteins employing a partial shape matching routine. After the identification of structures with matching pharmacophoric features and geometric shape, TrixP superimposes the binding sites and, finally, assesses their similarity according to the fit of pharmacophoric properties. TrixP is able to find analogies between closely and distantly related binding sites. Recovery rates of 81.8% for similar binding site pairs, assisted by rejecting rates of 99.5% for dissimilar pairs on a test data set containing 1331 pairs, confirm this ability. TrixP exclusively identifies members of the same protein family on top ranking positions out of a library consisting of 9802 binding sites. Furthermore, 30 predicted kinase binding sites can almost perfectly be classified into their known subfamilies.