Introduction: Chronic daily headache (CDH) represents a temporal profile of headache (15ays/month; 4ours/day; >6 months). We report the first comprehensive and largest levetiracetam (LEV) trial in CDH. Methods: A 27-week, multi-centre, randomised, placebo-controlled, cross-over, phase III B study assessed efficacy of a target of 3 g/day LEV of 6 placebo tablets/day in CDH. Primary efficacy was headache-free rate (HFR) while secondary parameters were loss of diagnostic criteria; severity; duration; disability; associated features; pain; and quality of life. Results: Ninety-six patients were recruited (baseline HFR 10.4 14.6%; median 0%). At onset of history 73 (74.1%) had migraine  aura and 35 (36.5%) had tension-type headache (TTH). Over the six months preceding recruitment 54 (56.3%) had migraine and 42 (43.8%) had TTH. Headache history was 22.6 15.0 years (median 20.0). Eighty-eight received placebo and 89 received LEV with >80 receiving stable dose in either arm. LEV achieved 3.9% increased HFR over placebo, showing a trend but not significance. There was 9.9% increase in loss of CDH diagnostic criteria re: headache days/month for LEV over placebo (p쮰325), reduced disability (p쮰487) and reduced pain severity for LEV (p쮰162). The Short-Form Quality of Life assessment instrument (SF-36) showed impaired mental health on LEV (p쮰01). Discussion: These findings conflict with reports of LEV efficacy, mandating placebo control in headache trials. Primary efficacy equated to one extra headache-free day/month with reduced disability and pain intensity. Mental health was reduced on LEV. The 10% loss of diagnostic criteria, decreased intensity and disability suggest a subpopulation with CDH where LEV remains a therapeutic option.