Rationale Stroke is a leading cause of death worldwide. Fever after stroke is a strong predictor of a poor outcome. Infections occur in up to 40% of patients with stroke and have also been associated with poor outcomes. Preventive antibiotic therapy lowers the infection rates in patients after stroke, as shown in a recent meta-analysis of randomised studies. Phase III trials evaluating the effect of antibiotic prophylaxis on clinical outcomes in sufficient numbers of patients with stroke have, however, not been performed to date. Ceftriaxone, an off-patent medicine, is an antibiotic with a broad defence against the bacteria that cause the most common infections after stroke. Preventive antibiotic therapy with ceftriaxone may potentially reduce poor outcome after acute stroke and, therefore, a randomised clinical trial is warranted. Aim The aim of the present study is to investigate whether the preventive use of the antibiotic ceftriaxone improves functional outcome in patients with stroke. Design We will conduct a multicentre prospective, randomised, open-label, blinded end point trial of standard care with preventive ceftriaxone treatment and compare it with standard care without preventive ceftriaxone. Study Adult patients with stroke (both ischaemic and haemorrhagic) and a score >= 1 on the National Institutes of Health Stroke Scale will be included. The 3200 patients will be randomly assigned to two groups of 1600 patients. One group will receive standard care and ceftriaxone at a dose of 2 g, given every 24 h intravenously for four-days, and the other group will receive stroke-unit care without preventive antibiotic treatment. Outcomes The primary end point will be functional outcome at a three-month follow-up on the modified Rankin Scale, dichotomised as a favourable outcome (0-2) or an unfavourable outcome (3-6). Secondary outcome measures will be death rate at discharge and three-months, infection rate during hospital admission, length of hospital admission, volume of poststroke care, use of antibiotics during the three-month follow-up, functional outcome using the full ordinal scoring range of the modified Rankin Scale, quality-adjusted life years and costs.