Thymosin‑alpha‑1 might lower death rates in people with severe infections (sepsis), but the evidence is mixed and the studies aren’t big enough to be sure. The benefit seems to vary by health condition, and the data aren’t strong enough to change everyday health routines.

Despite advances in understanding sepsis pathophysiology and extensive research, few treatments effectively target its underlying immune dysfunction. Thymosin &#x3b1;1 (T&#x3b1;1) shows promise as an immunomodulator, but its impact on sepsis remains unclear. A search strategy was designed to include any prospective clinical studies using T&#x3b1;1 for assessing 28-day mortality in patients with sepsis, excluding combination therapy studies. We conducted trial sequential analysis (TSA) to assess the robustness of meta-analyses findings. Heterogeneity of treatment effects (HTE) was conducted based on individual data from two multicenter randomized clinical trials (RCTs), with result credibility assessed through the instrument to assess the credibility of effect modification analyses (ICEMAN). Out of 3003 identified studies, 11 RCTs met the inclusion criteria (967 patients in T&#x3b1;1 group and 960 patients in control group). The comprehensive meta-analysis demonstrated a significant reduction in 28-day mortality associated with T&#x3b1;1 administration (OR 0.73, 95%CI: 0.59-0.90, <i>P</i> = 0.003). Nonetheless, analyses of high-quality (OR 0.82, 95%CI: 0.65-1.03, <i>P</i> = 0.09) and multi-center (OR 0.86, 95%CI: 0.68-1.08, <i>P</i> = 0.20) subgroups did not reveal a mortality benefit. The HTE analysis of multiple subgroups in two large RCTs (representing 75% of the total patients) showed heterogeneity. Potential benefits were noted in subgroups of cancer (moderate credibility), diabetes (low credibility), and coronary heart disease (low credibility). Furthermore, the trial sequential analysis (TSA) suggests that the current sample size is inadequate. T&#x3b1;1 has the potential to decrease 28-day mortality rates in patients with sepsis; however, it is crucial to recognize that its efficacy differs among various subgroups. These observations underscore the significance of personalized immunotherapy strategies in forthcoming clinical trials. https://www.crd.york.ac.uk/prospero/, identifier CRD42024628937.