Apart from single-limb knee extension, cardiorespiratory demand per kilogram work during low-load/high-repetition knee extension and shoulder flexion exercises was higher in patients with COPD than in healthy controls (range 27-122%, P < 0.0125). Δdeoxy-[Hb/Mb] of the quadriceps during knee extension was similar between the two groups, while Δdeoxy-[Hb/Mb] per kilogram work was higher in patients with COPD. We conclude that 1) in patients with COPD, single-limb exercises resulted in lower peak cardiorespiratory demand as well as higher localized workloads compared with two-limb exercises; 2) compared with healthy controls, the cardiorespiratory demand, either expressed per unit of work or relative to peak capacity, was higher in patients with COPD than in controls during low-load/high-repetition resistance exercises, irrespective of the involvement of one or two limbs or of the upper or lower extremity; 3) quadriceps muscle deoxygenation per unit of work during low-load/high-repetition knee extension was increased in COPD compared with controls; and 4) single- and two-limb low-load/high-repetition knee extension and shoulder flexion resistance exercises imposed a similar burden on the cardiorespiratory system, resulting in a higher cardiorespiratory demand per kilogram work performed during shoulder flexion compared with knee extension, in both COPD and healthy controls. NEW & NOTEWORTHY In chronic obstructive pulmonary disease (COPD), single-limb knee extension and shoulder flexion resulted in a lower peak cardiorespiratory response as well as larger localized exercise workloads compared with two-limb exercises. Cardiorespiratory and quadriceps deoxygenation cost per kilogram work was greater in COPD compared with healthy controls, despite similar acute responses. Compared with knee extension, shoulder flexion imposed a similar burden on the cardiorespiratory system in patients with COPD and healthy controls.