Objective: There is a widespread use of buffered crystalloid solutions in clinical practice. However, guidelines do not distinguish between specific types of buffered solutions and clinical equipoise exists. We aimed to assess the desirable and undesirable effects of acetate- versus lactate-buffered solutions in hospitalised patients. Methods: We conducted a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing the use of acetate- versus lactate-buffered solutions for intravenous administration in hospitalised adults and children. The primary outcome was all-cause short-term mortality. We adhered to our published protocol, the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Results: We included five RCTs enrolling 390 patients. We found no statistically significant difference in short-term mortality (random effects, risk ratio [RR] 0.29; 95% confidence interval [CI] 0.06–1.51, p =.14, I² = 0%) or hospital length of stay (LOS) (random effects, mean difference [MD]—1.31, 95% CI −3.66 to 1.05, p =.28, I² = 0%) between acetate- versus lactate-buffered solutions. The quality of evidence was very low. Data regarding intensive care unit LOS were reported by three trials and duration of vasopressor treatment by one trial; none of these data allowed for pooling in meta-analyses. No trials reported data on long-term mortality, health-related quality of life, adverse events, duration of mechanical ventilation or renal replacement therapy. Conclusion: In this systematic review, we found very low quantity and quality of evidence on the use of acetate- versus lactate-buffered solutions in hospitalised patients.