Objective: To evaluate the effect of acupuncture on the serum matrix metalloproteinase-2 (MMP-2) level and activity in patients with migraine. Methods: After baseline testing, eligible patients with migraine according to the criteria of the International Headache Society who volunteered to join the study were included (n=27). The patients received 10 sessions of acupuncture treatment. The points selected were bilateral ST8, ST44, LI4, LI11, LIV3, SP6, GB1, GB14, GB20, GV14, GV20, Yintang, Taiyang and ear Shenmen. Pain was measured using a visual analogue scale (VAS). Short form-36 (SF-36) was used to determine their quality of life. Blood samples were taken before treatment and after the first and last sessions of acupuncture for measurement of MMP-2 concentration and activity. Results: The mean VAS was 85.5±16.6 before acupuncture and was significantly decreased to 39.8±20.6 after 10 sessions of acupuncture (p<0.0001). There was a significant increase in all SF-36 scores after acupuncture compared with values before treatment (p<0.0001). No significant differences were found in MMP-2 concentrations before treatment and after the first and last sessions (p>0.05). However, there were significant changes in MMP-2 activity (p<0.0001). Conclusions: The results of this study showed a clinically relevant decrease in MMP-2 activity in patients with migraine treated with acupuncture. The mechanism underlying the effect of acupuncture in alleviating pain may be associated with a decrease in MMP-2 activity.