Background and Purpose— Recent studies indicate a possible beneficial effect on neuroregeneration and vascular protection of selective serotonin reuptake inhibitors after stroke. We conducted a national multicentre study to explore these effects. Methods— The TALOS study (The Efficacy of Citalopram Treatment in Acute Stroke) is a Danish placebo-controlled, randomized, double-blind study of citalopram started within 7 days after symptom onset to detect improvement in functional outcomes and cardiovascular protection in nondepressed, first-ever ischemic stroke. Study medication was given as add-on to standard medical care and treatment duration and follow-up was 6 months. There were 2 coprimary outcomes: changes in functional disability from 1 to 6 months on the modified Rankin Scale, and a composite vascular end point of transient ischemic attack/stroke, myocardial infarction, or vascular mortality during the first 6 months. Results— We enrolled 642 patients randomized to either citalopram (n=319) or placebo (n=323). Median National Institutes of Health Stroke Scale was 5.3 (range, 0–27) versus 4.8 (range, 0–28) at admission. Improvement in functional recovery from 1 to 6 months occurred in 160 (50%) patients on citalopram and 136 (42%) on placebo (odds ratio, 1.27; 95% CI, 0.92–1.74; P =0.057). When dropouts before 31 days were excluded (n=90), the analysis population showed an odds ratio of 1.37 (95% CI, 0.97–1.91; P =0.07). During a median follow-up of 150 days, 23 (7%) patients in the citalopram group and 26 (8%) patients in the placebo group had a primary, vascular end point (hazard ratio, 0.89; 95% CI, 0.50–1.60; P =0.24). A total of 28 patients (4%) died (16 versus 12; P =0.42) during the study. Conclusions— Early citalopram treatment did not improve functional recovery in nondepressed ischemic stroke patients within the first 6 months, although a borderline statistical significant effect was observed in the analysis population. The risk of cardiovascular events was similar between treatment groups, and citalopram treatment was well tolerated. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01937182. URL: https://www.clinicaltrialsregister.eu/ . EudraCT number: 2013-002253-30.