BACKGROUND: Potassium may be involved in the pathogenesis of migraine. Patients with chronic migraine and medication-overuse headache (CM-MOH) appear to be at a high risk for hypokalemia. METHODS: A retrospective cross-sectional study enrolled 139 consecutive patients with CM-MOH and 139 age- and sex-matched patients with healthy controls from our center. The demographic and clinical characteristics of the patients were recorded upon admission. The following morning, blood tests for potassium and magnesium concentrations were performed. RESULTS: The mean age of patients in the two groups was 48.60 ± 11.81 (CM-MOH) vs. 48.69 ± 11.99 (control). Migraineurs had a significantly lower serum potassium level (3.76 ± 0.35 mmol/L vs. 4.03 ± 0.30 mmol/L  < 0.001) and a higher prevalence of hypokalemia (21.6% versus 2.2%  < 0.001) compared to controls. A positive association between potassium and magnesium levels was observed in patients with CM-MOH ( = 0.25,  = 0.004). A slightly higher level of Mg (0.90 ± 0.06mmol/L versus 0.89 ± 0.05mmol/L,  = 0.012) was detected in the CM-MOH group compared to controls. According to logistic regression models, BMI was associated with the presence of hypokalemia in patients with CM-MOH. CONCLUSION: The incidence of hypokalemia in the control group was similar to that in the general population. An increased incidence of hypokalemia and lower serum potassium levels were observed in patients with CM-MOH. It is important to monitor the serum potassium levels in these patients.