Rolling resistance is one of the main forces resisting wheelchair propulsion and thus affecting stress exerted on the upper limbs. The present study investigates the differences in rolling resistance, propulsion efficiency and energy expenditure required by the user during power-assisted and manual propulsion. Different tire pressures (50%, 75%, 100%) and two different levels of motor assistance were tested. Drag force, energy expenditure and propulsion efficiency were measured in 10 able-bodied individuals under different experimental settings on a treadmill. Results showed that drag force levels were significantly higher in the 50%, compared to the 75% and 100% inflation conditions. In terms of wheelchair type, the manual wheelchair displayed significantly lower drag force values than the power-assisted one. The use of extra-power-assisted wheelchair appeared to be significantly superior to conventional power-assisted and manual wheelchairs concerning both propulsion efficiency and energy expenditure required by the user. Overall, the results of the study suggest that the use of power-assisted wheelchair was more efficient and required less energy input by the user, depending on the motor assistance provided.