Hypoxia is one of the major threats to the aquaculture sector resulting in substantial economic losses to the fish farmers. Thus, tolerance to hypoxia is of high economic interest to be genetically improved by breeding programs. Rainbow trout (Oncorhynchus mykiss) is one of the most cultured salmonid species worldwide, with welldeveloped breeding programs. Still, studies of genetic potential to improve hypoxia tolerance in this species are rare. In the present study, 1320 individuals of rainbow trout were used for a genome-wide association study of acute hypoxia tolerance based on imputed high-density genotypes to explore the genetic architecture and related candidate genes affecting hypoxia response. Three significant (Omy31_1, Omy31_2, Omy20) and two putative (Omy15, Omy28) quantitative trait loci (QTLs) were detected, but each of them only explained between 0.2% and 0.8% of the genetic variance of acute hypoxia tolerance. However, heritability was estimated at a moderate value of 0.24-0.28, that suggests a solid potential to improve hypoxia tolerance in the studied rainbow trout population by genetic selection. Moreover, it was shown that genomic prediction for hypoxia tolerance would lead to a relative increase of ~11% for genomic selection (GS) accuracy compared to the pedigree-based selection, considering a reference population of 1000 individuals. Finally, fifteen genes (ids, fmr1, arx, lonrf3, commd5, map4k4, smu1, b4galt1, re1, abca1, noa1, igfbp7, noxo1, bcl2a, mylk3) were proposed as potential functional candidates involved in hypoxia tolerance. Taking all proposed candidate genes (6 out of 15 genes) and high linkage disequilibrium (r 2) values within the main QTL (Omy31_1), we may hypothesize that the complex response to acute hypoxia in rainbow trout, i.e., the interplay between behavioural, morphological, and physiological responses, is primarily encoded by a supergene. However, further functional validation of their effects may help to specify the biological mechanisms triggering a response to acute hypoxia in rainbow trout.