Preterm birth elicits long-lasting physiological effects in various organ systems, potentially modulating exercise and environmental stress responses. To establish whether prematurely-born adults respond uniquely during early high-altitude acclimatization at rest and during exercise, 17 healthy adults born preterm (gestational age < 32 wk) and 17 term-born, age- and aerobic-capacity-matched, control participants completed a three-day high-altitude sojourn (3,375 m). Oxygen uptake, pulmonary ventilation, and hemodynamic responses, as well as pulse oxygen saturation, brain tissue saturation index (TSI), and skeletal muscle TSI, were measured daily at rest and during moderate-intensity steady-state exercise bouts. In general, the prematurely-born group displayed comparable acclimatization responses at rest, with similar ventilation and cardiac output observed between groups throughout. Resting brain TSI was, however, higher in the preterm group upon arrival at high altitude (72 ± 7% vs. 68 ± 3%; d = 1.20). Absolute exercising oxygen uptake was lower in the preterm participants (P = 0.047), with this group displaying lower exercising cardiac output underpinned by reduced stroke volume (both P = 0.035). Nevertheless, exercising minute ventilation (V̇e) did not differ between groups (P = 0.237) while brain TSI (70 ± 6% vs. 66 ± 3%; d = 1.35) and pulse oxygen saturation (85 ± 3% vs. 82 ± 5%; d = 1.52) were higher with prematurity upon arrival to high altitude. These findings suggest that healthy prematurely-born adults exhibit comparable early acclimatization patterns to their term-born counterparts and better maintain cerebral oxygenation at rest. Together, these data suggest that prematurely-born adults should not be discouraged from high-altitude sojourns involving physical activity.NEW & NOTEWORTHY The acclimatization pattern across three days at 3,375 m, at rest and during moderate-intensity exercise, was similar between healthy adults born prematurely and their term-born counterparts. Preterm adults free from respiratory complications were found to better maintain brain tissue and capillary oxygen saturation at high altitudes, whereas the term-born group experienced larger altitude-induced reductions. Despite apparent cardiac limitations, preterm individuals tolerated exercise similarly to their term-born peers. These findings underscore the notion that preterm birth per se does not predispose healthy adults to decreased altitude tolerance during exercise.