Background Levetiracetam and zonisamide are licensed as monotherapy for focal epilepsy, but there is uncertainty as to whether they should be recommended as first line treatments due to lack of evidence of clinical and cost effectiveness. Methods This randomised un-blinded controlled trial compared starting treatment with levetiracetam, zonisamide or lamotrigine for newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older with two or more unprovoked focal seizures. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide compared to lamotrigine for the primary outcome time to 12 month remission. The non-inferiority limit was a Hazard Ratio (HR) of 1·329, which equates to an absolute difference of 10%. HR > 1 indicates an event is more likely on lamotrigine. Findings 990 participants were recruited between April 2013 and June 2017 and followed up for a further 2 years; mean age 39·3 years (range 5·0 – 91·9), males 56·7%, median number of pre-randomisation seizures 6 (IQR 3 - 24). Levetiracetam did not meet the criteria for non-inferiority in the intention to treat analysis of time to 12-month remission HR versus lamotrigine 1·19 (97·5% CI 0·95 to 1·47) but zonisamide did HR versus lamotrigine of 1·03 (97·5% CI 0·83 to 1·28). The per-protocol analysis showed superiority of lamotrigine over both levetiracetam, HR 1·32 (95% CI 1·05 to 1·66), and zonisamide, HR 1·37 (95% CI 1·08 to 1·73). For time to treatment failure (any reason), lamotrigine was superior to levetiracetam, HR 0·60 (95% CI 0·46 to 0·77), and zonisamide, HR 0·46 (95% CI 0·36 to 0·60). Treatment failure due to adverse reactions was significantly less likely with lamotrigine than levetiracetam, HR 0·53 (HR 95% CI 0·35 to 0·79), and zonisamide, HR 0·37 (95% CI 0·25 to 0·55). Adverse reactions were reported by 33% participants starting lamotrigine, 44% levetiracetam and 45% zonisamide. Lamotrigine dominated both levetiracetam and zonisamide in the cost-utility analysis, with a higher net health benefit of 1·403 (97·5% Central Range (CR) 1·319, 1·458) compared with 1·222 (1·110, 1·283) and 1·232 (1·112, 1·307), respectively, at a cost-effectiveness threshold of £20,000 per QALY. Interpretation These findings do not support the use of levetiracetam or zonisamide as first line treatments for focal epilepsy.