We evaluate various methods to estimate pairwise statistical significance of a pairwise local sequence alignment in terms of statistical significance accuracy and compare it with popular database search programs in terms of retrieval accuracy on a benchmark database. Results indicate that using pairwise statistical significance using standard substitution matrices is significantly better than database statistical significance reported by BLAST and PSI-BLAST, and that it is comparable and at times significantly better than SSEARCH. An application of pairwise statistical significance to empirically determine effective gap opening penalties for protein local sequence alignment using the widely used BLOSUM matrices is also presented.