Background: Respiratory tract infection (RTI) is associated with a higher risk of kidney failure in patients with chronic kidney disease (CKD), without effective precautions. Self-administered acupressure (SAA) has been shown to potentially prevent RTI, but still lack of clinical evidence in CKD. The present randomized controlled trial assessed the efficacy and safety of SAA in preventing RTI recurrence in patients with CKD. Methods: Participants with CKD who had been diagnosed with RTI on more than 2 occasions in the preceding 12 months were enrolled between November 6, 2017, and August, 6, 2018. They were randomly assigned (1:1) to receive daily SAA combined with usual care (intervention) or usual care alone (control) for 24 months. The primary outcome was time to first RTI. Secondary outcomes were RTI rate, kidney function, proteinuria and serum immune indicators, detected by the clinical laboratory in the hospital. The study would be discontinued if the participant met the criteria of stopping the study. Kaplan-Meier method and multivariable Cox proportional hazards regression were used to compare the primary outcome between the two groups. Results: Among the 540 patients screened, 114 participants were randomly assigned to the intervention group (n=57) or the control group (n=57). The median follow-up duration was 24.4 months. Compared with controls, participants in the intervention group did not have a significantly lower risk of RTI according to Kaplan-Meier analysis, but did have a significantly lower risk of RTI according to competing risk analysis (HR 0.65, 95% CI: 0.42-1.00; P=0.05), when considering endpoint (dialysis or death) and loss to followup as competing risks, and had a significantly lower rate of RTI (1.65 vs. 2.19 episodes per patient-year, respectively; incidence rate ratio (IRR) 0.75, 95% CI: 0.62-0.92; P=0.006). Apart from lower study serum IgG levels in the intervention group at 24 months (mean difference 0.68 g/L; 95% CI: 0.07-1.29; P=0.029), all other secondary outcomes and overall adverse events were comparable between the 2 groups. Conclusions: SAA is a promising effective and safe therapy for preventing RTI in patients with CKD. However, the efficacy of SAA in children and adolescents still needs further study. Trial registration: Chinese Clinical Trials Registry ChiCTR-IOR-17012654