Introduction: Hydroxyethyl starch (HES) 130/0.38-0.45 is a synthetic colloid, which has been on the market since 1999. In recent years, concern about the use of HES has been raised because of serious adverse events, including acute kidney injury, bleeding and even increased mortality with its use. In the outlined systematic review, we aim to assess if the adverse effects of HES 130/0.38-0.45 in patients with sepsis could have been discovered earlier. Methods: We will conduct a systematic review with meta-analysis of randomised clinical trials in animals and patients and observational studies in patients comparing HES 130/0.38-0.45 vs any crystalloid in sepsis. The primary outcome will be all-cause mortality at longest follow-up. We will systematically search EMBASE, MEDLINE and the Cochrane Library for relevant literature. We will follow the recommendations by the Cochrane Handbook, the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Discussion: With the outlined systematic review, we aim to assess whether the adverse effects of HES 130/0.38-0.45 could have been discovered earlier by comparing summary effect estimates of harm from observational studies in patients and randomised trials in animals and patients. The results may have implications for future drug development and approval processes.