Purpose: To examine the effects of rear-wheel camber on the physiological and biomechanical responses during manual wheelchair propulsion in highly trained wheelchair athletes. Methods: Participants (N = 14) pushed on a motorized treadmill (2.2 m·s-1, 0.7% gradient) in four standardized camber conditions (15°, 18°, 20°, and 24°). Standardization was achieved by controlling seat height, the distance between top dead center of the main wheels and "toe-in toe-out" across all camber settings. Power output (PO) and cardiorespiratory measures were collected for each camber setting. Three-dimensional upper body joint kinematics were also analyzed via two high-speed video cameras (100 Hz). One-way ANOVA with repeated measures was applied to all data with statistical significance accepted when P < 0.05. Results: A significantly higher PO was observed for 24° camber (24.3 W) in relation to 15° (20.3 W) and 18° (21.3 W), and also for 20° (23.3 W) in relation to 15°. This resulted in an improvement in mechanical efficiency (ME) for both 24° (6.8%) and 20° (6.7%) compared with 15° (5.9%). However, significantly higher oxygen uptake (reduced economy) and HR responses were observed for 24° (1.04 L·min-1; 105 bpm) compared with 15° (0.98 L·min-1; 102 bpm) and 18° (0.97 L·min-1; 102 bpm). Also, significantly greater ranges of motion were established for shoulder flexion and elbow extension during the push phase for 24° and were likely to have contributed toward the increased oxygen cost in this setting. Conclusions: This study revealed that 20° and 24° camber improved the ME of wheelchair propulsion in highly trained wheelchair athletes, yet these increased external power requirements and reduced the economy.