Clickers are catching growing attention in education. This study, using data collected from a questionnaire, forty content words, and a vocabulary knowledge scale, aims to identify if clickers can enhance EFL (English as a foreign language) vocabulary knowledge and raise students' satisfaction level compared with the traditional multimedia-based instruction. Gender differences were also explored. Data from 115 EFL learners showed that: (1) Clickers-based instruction significantly increased participants' satisfaction level compared with traditional multimedia-based instruction in an EFL class; (2) Clickers-based instruction significantly enhanced participants' vocabulary knowledge compared with traditional multimedia-based instruction in an EFL class; (3) Males were significantly more satisfied with clickers-based instruction than females in an EFL class and there were no significant gender differences in satisfaction levels under multimedia-based instruction; (4) Males obtained significantly more vocabulary knowledge than females under clickers-based instruction, while females obtained significantly more vocabulary knowledge than males under multimedia-based instruction.