MOTIVATION: Recently, the number of available protein tertiary structures and compounds has increased. However, structure-based virtual screening is computationally expensive owing to docking simulations. Thus, methods that filter out obviously unnecessary compounds prior to computationally expensive docking simulations have been proposed. However, the calculation speed of these methods is not fast enough to evaluate ≥ 10 million compounds. RESULTS: In this article, we propose a novel, docking-based pre-screening protocol named Spresso (Speedy PRE-Screening method with Segmented cOmpounds). Partial structures (fragments) are common among many compounds; therefore, the number of fragment variations needed for evaluation is smaller than that of compounds. Our method increases calculation speeds by ∼200-fold compared to conventional methods. AVAILABILITY AND IMPLEMENTATION: Spresso is written in C ++ and Python, and is available as an open-source code (http://www.bi.cs.titech.ac.jp/spresso/) under the GPLv3 license. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.