To support that myofascial pain syndrome (MPS) of gastrocnemius muscle is one cause of nocturnal calf cramps, quantitative assessment of the efficacy of trigger point (TrP) injection compared with oral quinine in the treatment of nocturnal calf cramps (NCC) associated with MPS of gastrocnemius muscle was designed. Twenty four subjects with NCC and gastrocnemius TrPs were randomly divided into two groups of twelve for each treatment. Patients in group 1 were treated with xylocaine injection at the gastrocnemius TrP, and 300 mg of quinine sulfate p.o. was prescribed for patients of group 2. The treatment period was four weeks with a follow-up 4 weeks later. Cramps were assessed quantitatively (in terms of frequency, duration, pain intensity, cramp index, and pain threshold of the gastrocnemius TrPs) before treatment, after treatment and at the end of the follow-up respectively. The outcome of treatment in both groups showed a statistically significant reduction in all quantitative aspects of cramps (95% confidence interval). Also the pain threshold of the gastrocnemius TrP was significantly increased in group 1 only when comparing the pre-treatment and at the end of follow-up. In comparing the two groups we found no statistical difference during the period of treatment. The benefit of both strategies lasted up to four weeks following cessation of the treatment but the outcome of all measures (except pain threshold) were found to be significantly better in the group treated with TrP injection. The results of this study support that gastrocnemius trigger point is one cause of NCC and show that the TrP injection strategy for NCC associated with myofascial pain is not only as effective as oral quinine during the treatment period but also better in the prolonged effect at follow-up.