Rationale Selective Serotonin Reuptake Inhibitors (SSRI) are effective in the treatment of post-stroke depression and may have potential neuroprotective and vascular effects. Data from registry studies have further indicated a protective effect against recurrent ischemic events, but also an increased risk of bleeding in patients with ischemic stroke. Therefore, prospective studies are needed to determine the effects of SSRI treatment after acute ischemic stroke. Aims and design TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double-blind trial testing citalopram in acute ischemic stroke. We hypothesize that citalopram treatment initiated in the acute phase after ischemic stroke will improve outcome assessed by the modified Rankin Score (mRS) and reduce the risk of death from vascular causes, transient ischemic attack (TIA)/stroke and myocardial infarction. Study outcomes There are two co-primary effect variables: (i) Functional status at six-months, measured by the modified Rankin Scale, and (ii) Vascular death, TIA/stroke and myocardial infarction. Secondary effect variables include: (i) Single primary outcomes; (ii) The Barthel Index; (iii) Mini Mental State Examination at six-months; (iv) Final infarct size (Magnetic Resonance Imaging). Discussion SSRI treatment is well tolerated and overall beneficial in the wake of stroke; it may also be neuroprotective and prevent new vascular events.