Background <p>Stroke-associated pneumonia (SAP) is one of the most common complications in acute ischemic stroke (AIS) patients, affecting 8.5% to nearly 30% of cases and significantly impacting both mortality and long-term survival. As it is closely related to worse outcome, exploring effective preventive strategies, such as remote ischemic conditioning (RIC), is essential for reducing SAP incidence and improving patient outcomes. This study aims to compare the efficacy and safety of RIC for preventing SAP in patients with ischemic stroke within 24 h of symptom onset.</p> Methods and design <p>RICA-2 is a multicenter, randomized, double-blind, parallel-controlled, phase III clinical trial in China. This study will enroll an estimated 1650 patients aged ≥ 18 years within 24 h after AIS symptom onset, with National Institutes of Health Stroke Scale ⩾ 4. The patients will be randomly assigned to RIC or Sham-RIC (1:1) and will be treated with cuff inflation at 200 mmHg or 60 mmHg, respectively. This procedure will be administered twice daily for seven consecutive days. The primary efficacy endpoint is SAP incidence rate. Safety incidence will be recorded and reported.</p> Discussion <p>RIC has broad clinical application prospects and may play a preventive role in stroke-related pneumonia. RICA-2 is designed to verify whether RIC treatment can serve as an adjuvant therapy for preventing stroke-associated pneumonia and to identify safety concerns.</p> Trial registration <p>ClinicalTrials.gov NCT05982015. Registered on January 22, 2024.</p>