Oxygen is critical to normal brain functioning and development. In high altitude where the oxygen concentration and pressure are very low, human cognitive capability such as working memory has been found to be jeopardized. Such effect might persist with long-term high-altitude residence. The current study investigated the verbal working memory of 28 high-altitude residents with blood level oxygen dependent (BOLD) functional magnetic resonance imaging (fMRI), in contrast with that of the 30 sea level residents. All of the subjects were healthy college students, matched on their age, gender ratio and social-economic status; they also did not show any difference on their hemoglobin level. The high-altitude subjects showed longer reaction time and decreased response accuracy in behavioral performance. Both groups showed activation in the typical regions associated with the 2-back verbal working memory task, and the behavioral performance of both groups showed significant correlations with the BOLD signal change amplitude and Granger causality values (as a measure of the interregional effective connectivity) between these regions. With group comparison statistics, the high-altitude subjects showed decreased activation at the inferior and middle frontal gyrus, the middle occipital and the lingual gyrus, the pyramis of vermis, as well as the thalamus. In conclusion, the current study revealed impairment in verbal working memory among high-altitude residents, which might be associated with the impact of prolonged chronic hypoxia exposure on the brain functionality.