To determine the efficacy and safety of quinine in treating nocturnal muscle cramps we performed a double-blind, placebo-controlled, parallel-group, multicentre trial in 17 general practice centres in Germany. Ninety-eight patients aged 18-70 years with more than six muscle cramps in two weeks were enrolled. A two-week run-in period without treatment was followed by two weeks of treatment with 400 mg quinine or placebo per day and a wash-out period of two weeks without treatment. The primary outcome measure was the reduction in the number of muscle cramps between the run-in and treatment periods. The intensity of cramps, number of nights with cramps, sleep disturbance and intensity of pain were recorded as secondary outcome measures. At baseline the median number of cramps was 12 in two weeks in both groups. The median reduction between the run-in and therapy phases was eight (95% CI 7-10) versus six (95% CI 3-7) muscle cramps during quinine and placebo treatment; 36 (80%) participants in the quinine group and 26 (53%) in the placebo group had a reduction of at least 50% in the number of muscle cramps. Frequency, intensity and pain at night showed a statistically significant difference in favour of quinine. The improvement was more evident according to physician assessment than patient assessment; this is corroborated by the high placebo response rate. No significant differences were found between the two groups with respect to side-effects. Short term treatment with 400 mg quinine per day can effectively prevent nocturnal leg cramps in adults without relevant side-effects.