Several previous genomic studies have focused on adaptation tohigh elevations, but these investigations have been largely limitedto endotherms. Snakes of the genus Thermophis are endemic tothe Tibetan plateau and therefore present an opportunity to studyhigh-elevation adaptations in ectotherms. Here, we report the denovo assembly of the genome of a Tibetan hot-spring snake (Ther-mophis baileyi) and then compare its genome to the genomes ofthe other two species of Thermophis, as well as to the genomes oftwo related species of snakes that occur at lower elevations. Weidentify 308 putative genes that appear to be under positive se-lection in Thermophis. We also identified genes with shared aminoacid replacements in the high-elevation hot-spring snakes com-pared with snakes and lizards that live at low elevations, includingthe genes for proteins involved in DNA damage repair (FEN1) andresponse to hypoxia (EPAS1). Functional assays of the FEN1 allelesreveal that the Thermophis allele is more stable under UV radia-tion than is the ancestral allele found in low-elevation lizards andsnakes. Functional assays of EPAS1 alleles suggest that the Ther-mophis protein has lower transactivation activity than the low-elevation forms. Our analysis identifies some convergent geneticmechanisms in high-elevation adaptation between endotherms(based on studies of mammals) and ectotherms (based on ourstudies of Thermophis).