As an advanced interaction mode, the gesture has been widely used for the human-computer interaction (HCI). The paper proposes a comfort evaluation model based on the mechanical energy expenditure (MEE) and the mechanical efficiency (ME) to predict the comfort of gestures. The proposed comfort evaluation model takes nineteen muscles and seven degrees of freedom into consideration based on the data of muscles and joints and is capable of simulating the MEE and the ME of both static and dynamic gestures. The comfort scores (CSs) can be therefore calculated by normalizing and assigning different decision weights to the MEE and the ME. Compared with the traditional comfort prediction methods based on measurement, on the one hand, the proposed comfort evaluation model makes it possible for providing a quantitative value for the comfort of gestures without using electromyography (EMG) or other measuring devices; on the other hand, from the ergonomic perspective, the results provide an intuitive indicator to predict which act has the higher risk of fatigue or injury for joints and muscles. Experiments are conducted to validate the effectiveness of the proposed model. According to the comparison result among the proposed comfort evaluation model, the model based on the range of motion (ROM) and the model based on the method for movement and gesture assessment (MMGA), a slight difference can be found due to the ignorance of dynamic gestures and the relative kinematic characteristics during the movements of dynamic gestures. Therefore, considering the feedback of perceived effects and gesture recognition rate in HCI, designers can achieve a better optimization for the gesture design by making use of the proposed comfort evaluation model.