: In biological sequence analysis, position specific scoring matrices (PSSMs) are widely used to represent sequence motifs. In this paper, we present a new nonheuristic algorithm, called ESAsearch, to efficiently find matches of such matrices in large databases. Our approach preprocesses the search space, e.g. a complete genome or a set of protein sequences, and builds an enhanced suffix array which is stored on file. The enhanced suffix array only requires 9 bytes per input symbol, and allows to search a database with a PSSM in sublinear expected time. We also address the problem of non-comparable PSSM-scores by developing a method which allows to efficiently compute a matrix similarity threshold for a PSSM, given an E-value or a p-value. Our method is based on dynamic programming. In contrast to other methods it employs lazy evaluation of the dynamic programming matrix: it only evaluates those matrix entries that are necessary to derive the sought similarity threshold. We tested algo...