ABSTRACT: When watching someone performs an action, mirror neurons are activated in a way that is very similar to the activation that occurs when actually performing that action. Previous single-sample case studies indicate that hand-action observation training may lead to activation and remodeling of mirror neuron systems, which include important language centers, and may improve language function in aphasia patients. In this randomized-block-design experiment, we recruited 24 aphasia patients from, Zhongda Hospital, Southeast University, China. The patients were divided into three groups where they underwent hand-action observation and repetition, dynamic-object observation and repetition, or conventional speech therapy. Training took place 5 days per week, 35 minutes per day, for 2 weeks. We assessed language function via picture naming tests for objects and actions and the Western Aphasia Battery. Among the participants, one patient, his wife and four healthy student volunteers underwent functional magnetic resonance imaging to analyze changes in brain activation during hand-action observation and dynamic-object observation. Results demonstrated that, compared with dynamic-object observation, hand-action observation led to greater performance with respect to the aphasia quotient and affiliated naming sub-tests and a greater Western Aphasia Battery test score. The overall effect was similar to that of conventional aphasia training, yet hand-action observation had advantages compared with conventional training in terms of vocabulary extraction and spontaneous speech. Thus, hand-action observation appears to more strongly activate the mirror neuron system compared with dynamic-object observation. The activated areas included Broca's area, Wernicke's area, and the supramarginal gyrus. These results suggest that hand-action observation combined with repetition might better improve language function in aphasia patients compared with dynamic-object observation combined with repetition. The therapeutic mechanism of this intervention may be associated with activation of additional mirror neuron systems, and may have implications for the possible repair and remodeling of damaged nerve networks. The study protocol was approved by the Ethical Committee of Nanjing Medical University, China (approval number: 2011-SRFA-086) on March 11, 2011. This trial has been registered in the ISRCTN Registry (ISRCTN84827527).