BACKGROUND: Pleural infections are common and drainage of the pleural space, in addition to antimicrobial therapy, is often required for adequate treatment. Guidelines suggest flushing small bore chest drains with 20-30 mL of saline every six hours, however, no randomized controlled trials (RCTs) have assessed if this practice improves outcomes for pleural space infections. As a result, flushing practice is varied, inconsistent, and confounds the interpretation of studied therapeutic modalities in pleural space infection trials. The impact of regular chest drain flushing compared to as-needed flushing on length of time to chest tube removal is unclear. METHODS: Chest Drain REgular FLushing in ComplIcated Parapneumonic EFfusions and Empyemas (RELIEF) is a multi-center, open label randomized controlled trial conducted in the United States. Patients with a pleural space infection requiring chest drain placement for inpatient management will be screened for eligibility. Patients will be randomized within 24 hours of chest drain placement to a regular flushing protocol versus as-needed flushing for drain blockage. The primary outcome is time from randomization until time to chest drain removal (hours). Secondary outcomes are length of hospitalization, degree of radiographic improvement by chest X-ray, ultrasound or CT scan from time of drain placement to time of removal, need for additional procedures for the management of pleural space infection, and complications. An ordinal, multi-state transition model will be used to precisely characterize the role of flushing in longitudinal clinical outcomes in the two arms. DISCUSSION: RELIEF is a multi-center, open label randomized controlled trial that compares a regular saline flushing protocol with as-needed saline flushing of small-bore chest drains (8-20Fr) for the management of pleural space infection. This will be the first randomized controlled trial evaluating flushing protocol with patient-centered outcomes in pleural space infections. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov (NCT06427538) on 05-10-2024.