The purpose of this study was to compare submaximal physiological responses (oxygen uptake, ventilation, heart rate) and gross mechanical efficiency between synchronous and asynchronous hand cycling at different cadences. Thirteen non-disabled men (22.4 ± 1.6 yr) performed two submaximal exercise tests on a treadmill, using synchronous and asynchronous crank settings in counter balanced order. Tests were performed using a commercially available hand cycle unit that was attached to a hand rim wheelchair. Each test consisted of five 5-min exercise bouts at 36, 47, 55, 65, and 84 rpm. ANOVA for repeated measures showed a significant effect of crank mode (p < 0.001) and cadence (p < 0.001), as well as an interaction effect between both (p < 0.01). Physiological responses were lower, and efficiency higher, in synchronous versus asynchronous hand cycling at all cadences. Post-hoc analysis of the (overall) effect of cadence showed significantly higher physiological responses and lower efficiency at the higher (84 vs. 65 rpm and 65 vs. 55 rpm) and lower (36 vs. 47 rpm) cadences. The interaction effect indicates that the effect of crank mode was dependent on cadence, showing a larger difference between synchronous and asynchronous hand cycling at 84 vs. 65 rpm and at 36 vs. 47 rpm. It is concluded that, in contrast to previous results in arm crank ergometry, synchronous hand cycling is less strenuous and more efficient than asynchronous hand cycling.