Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥ 21 g dl-1 in adult males) is a maladaptive pathology associated with increased cardiovascular risk in Andean highlanders (Corante et al. (2018)). It has been demonstrated that flow-mediated dilation (FMD) in response to a transient increase in shear stress is reduced in Andeans with EE (Tremblay et al. (2019)); however, whether a similar impairment in response to more commonly encountered sustained increases in shear stress occurs is unknown. We sought to characterize sustained shear stress stimulus FMD (SS-FMD) in response to progressive handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4330 m). Male Andean highlanders with (n=17, [Hb] = 23.2 ± 1.2 g dl-1 (mean ± SD)) and without EE (n=23, [Hb] = 18.7±1.9 g dl-1) performed three-minutes of rhythmic handgrip exercise at intensities of 20%, 35%, and 50% of their maximum voluntary contraction (MVC). Duplex ultrasound was used to record brachial artery blood velocity and diameter in the last minute of each handgrip intensity. Venous whole blood viscosity was assessed to calculate shear stress. Although baseline shear stress and shear stress at 20% and 35% MVC did not differ between cohorts, Andeans with EE had a 22% lower shear stress at 50% MVC compared to Andeans without EE (P=0.004). At 20% MVC, SS-FMD did not differ between groups, however at 35 % and 50 % MVC, SS-FMD was 2.1 ± 2.0% and 2.8 ± 2.7% in Andeans with EE compared to 4.1 ± 3.4% and 7.5 ± 4.5% in those without EE (P = 0.048 and P < 0.001). The stimulus-response slope (change in shear stress versus change in diameter) was lower in Andeans with EE compared to Andeans without EE (P = 0.028). When participants were pooled, this stimulus-response slope was negatively related to Hb (r2 = 0.203, P = 0.0035) and blood viscosity (r2 = 0.148, P = 0.014), and positively related to oxyhemoglobin saturation (r2 = 0.136, P = 0.019). These findings report, for the first time, an impaired SS-FMD in response to small muscle mass exercise in Andeans with EE. Exercise results in a physiologically-relevant and commonly encountered shear stress stimulus, and in combination with results indicating impaired FMD in response to transient increases in shear stress, these findings suggest a generalized reduction in endothelial sensitivity to shear stress in this population.