The taxonomic status of the medically important spider genus Loxosceles Heineken et Lowe, 1832 (Sicariidae) in Iran, Turkmenistan, and Afghanistan is revised. Two species are described as new to science: Loxosceles coheni sp. n. (♂♀, southwestern Iran) and Loxosceles turanensis sp. n. (♂♀, southern Turkmenistan and eastern Iran). Additionally, Loxosceles alicea Gertsch, 1967 syn. n. (♀, Peru) is synonymized with Loxosceles rufescens (Dufour, 1820). The local distribution of all treated species is mapped (including several new records), and reported cases of loxoscelism from this region are briefly reviewed., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)