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Abstract SummaryMultiple sequence alignment is an important problem in computational biology with applications that include phylogeny and the detection of remote homology between protein sequences. UPP is a popular software package that constructs accurate multiple sequence alignments for large datasets based on ensembles of hidden Markov models (HMMs). A computational bottleneck for this method is a sequence-to-HMM assignment step, which relies on the precise computation of probability scores on the HMMs. In this work, we show that we can speed up this assignment step significantly by replacing these HMM probability scores with alternative scores that can be efficiently estimated. Our proposed approach utilizes a multi-armed bandit algorithm to adaptively and efficiently compute estimates of these scores. This allows us to achieve similar alignment accuracy as UPP with a significant reduction in computation time, particularly for datasets with long sequences. Availability and implementationThe code used to produce the results in this paper is available on GitHub at: https://github.com/ilanshom/adaptiveMSA.