--- - |2+ Key points The reduced oxygen tension of high altitude compromises performance in lowlanders. In this environment, Sherpa display superior performance, but little is known on this issue. Sherpa present unique genotypic and phenotypic characteristics at the muscular level, which may enhance resistance to peripheral fatigue at high altitude compared to lowlanders. We studied the impact of gradual ascent and exposure to high altitude (5050 m) on peripheral fatigue in age‐matched lowlanders and Sherpa, using intermittent electrically‐evoked contractions of the knee extensors. Peripheral fatigue (force loss) was lower in Sherpa during the first part of the protocol. Post‐protocol, the rate of force development and contractile impulse recovered faster in Sherpa than in lowlanders. At any time, indices of muscle oxygenation were not different between groups. Muscle contractile properties in Sherpa, independent of muscle oxygenation, were less perturbed by non‐volitional fatigue. Hence, elements within the contractile machinery contribute to the superior physical performance of Sherpa at high altitude. Abstract Altitude‐related acclimatisation is characterised by marked muscular adaptations. Lowlanders and Sherpa differ in their muscular genotypic and phenotypic characteristics, which may influence peripheral fatigability at altitude. After gradual ascent to 5050 m, 12 lowlanders and 10 age‐matched Sherpa (32 ± 10 vs. 31 ± 11 years, respectively) underwent three bouts (separated by 15 s rest) of 75 intermittent electrically‐evoked contractions (12 pulses at 15 Hz, 1.6 s between train onsets) of the dominant leg quadriceps, at the intensity which initially evoked 30% of maximal voluntary force. Trains were also delivered at minutes 1, 2 and 3 after the protocol to measure recovery. Tissue oxygenation index (TOI) and total haemoglobin (tHb) were quantified by a near‐infrared spectroscopy probe secured over rectus femoris. Superficial femoral artery blood flow was recorded using ultrasonography, and delivery of oxygen was estimated (eDO2). At the end of bout 1, peak force was greater in Sherpa than in lowlanders (91.5% vs. 84.5% baseline, respectively; P < 0.05). Peak rate of force development (pRFD), the first 200 ms of the contractile impulse (CI200), and half‐relaxation time (HRT) recovered faster in Sherpa than in lowlanders (percentage of baseline at 1 min: pRFD: 89% vs. 74%; CI200: 91% vs. 80%; HRT: 113% vs. 123%, respectively; P < 0.05). Vascular measures were pooled for lowlanders and Sherpa as they did not differ during fatigue or recovery (P < 0.05). Mid bout 3, TOI was decreased (90% baseline) whereas tHb was increased (109% baseline). After bout 3, eDO2 was markedly increased (1266% baseline). The skeletal muscle of Sherpa seemingly favours repeated force production at altitude for similar oxygen delivery compared to lowlanders. - 'The Journal of Physiology, Volume 596, Issue 22, Page 5365-5377, 15 November 2018. '