Background Each year, five million people are left disabled after stroke. Upper -extremity (UE) dysfunction is a leading problem. Neuroplasticity can be enhanced by non-invasive brain stimulation (NIBS) but evidence from large, randomized multicenter trials is lacking. We aimed at demonstrating efficacy of NIBS to enhance motor recovery after ischemic stroke. Methods We randomly assigned patients to receive anodal transcranial direct current (tDCS, 1 mA, 20 min) or placebo stimulation ('control') over the primary motor cortex of the lesioned hemisphere in addition to standardized rehabilitative training over ten days in the subacute phase after stroke. The original study was planned to enrol 250 but, following a blinded interim analysis, ended with 123 participants. The primary outcome parameter was UE impairment, measured by UE-Fugl-Meyer-Assessment (UEFMA), one to seven days after the end of the treatment intervention (ClinicalTrials.gov, NCT00909714). Findings From 2009 to 2019,123 patients were included, with 119 entering intention -to -treat analysis (ITT). The control group (N = 61) improved 8.9 (SD 7.7) UEFMA points, the tDCS group (N = 58) improved 9.0 (8.8) points. ITT was neutral with respect to the primary efficacy endpoint (p = 0.820). We found no difference in UEFMA change between active tDCS and control. The safety profile of tDCS was favorable. In particular, there were no seizures. Interpretation In patients with ischemic stroke, anodal tDCS applied to the motor cortex of the lesioned hemisphere over 10 days in the subacute phase was safe but did not improve the recovery of upper extremity function compared with placebo stimulation. 2024;38: