We tested low-dose naltrexone/acetaminophen combination for episodic migraine prevention . We randomly assigned patients to naltrexone/acetaminophen (n=6) or placebo (n=6) for a 12-week double-blind treatment . Non-responders continued into open-label treatment with naltrexone/acetaminophen (n=5) for additional 12 weeks . Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline . The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period . The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period . The magnitude of the treatment effect for naltrexone/acetaminophen observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7 %) naltrexone/acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7 %) placebo-treated patients (p=0.09). In the open-label phase, treatment with naltrexone/acetaminophen (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days . Adverse events were mild/moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery . We postulate that naltrexone's toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines' production in the trigeminal ganglion averting``overactive nerves"and migraine . Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), we postulate mid-dose naltrexone (MDN) (defined as 6 - 10 mg/day) may offer a greater migraine prevention control.