High-altitude hypoxia, or the decrease in oxygen levels caused by lowered barometric pressure, challenges the ability of humans to live and reproduce. Human physiological responses to high-altitude have been extensively documented among long-term high-altitude residents (i.e. Andeans and Tibetans). Furthermore, recent research has begun to unravel the genetic bases for the observed physiological traits. Among Andeans, genome scans for natural selection have identified several selection nominated candidate genes or gene regions for high-altitude adaptation. This includes several genes that are part of the hypoxia inducible transcription factor (HIF) pathway involved in oxygen sensing and metabolism as well as genomic regions with previously unknown function with respect to altitude phenotypes. In order to explore selection nominated candidate SNP genotype associations with particular altitude phenotypes, we conducted genotype-phenotype association studies among Peruvian Quechua. Our subject participants included Quechua who were lifelong sea level residents transiently exposed to hypobaric hypoxia and Quechua who were lifelong residents of high-altitude. Significant associations were identified for the higher arterial hemoglobin-oxygen saturation (SaO2) observed at rest and during exercise among Quechua. These results provide key insights into the patterns of genetic adaptation to high altitude in Andean populations, shed light on variants controlling this complex phenotype, and are of potential importance for public health given HIF-pathway involvement with various disease processes, e.g., regulation of tumor growth.