Sepsis is the most common critical disease with high mortality in intensive care unit. Platelet count (PC) frequently altered in sepsis patients and implicated in the pathogenesis of multi-organ failure. It is also worth mentioning that thrombocytopenia was closely associated with poor outcomes in sepsis patients. However, whether drug intervention aimed at correcting thrombocytopenia would improve the prognosis of sepsis patients and which kind of sepsis patients could benefit from this therapy is still unclear. This study aims to explore the effect of severe thrombocytopenia on the prognosis of sepsis and the impact of a platelet-elevating drug (recombinant human thrombopoietin, rhTPO) for these sepsis patients. In this study, we included 249 sepsis patients diagnosed by sepsis 3.0, and these patients were classified into the three groups based on PC: normal (PC ≥ 100 × 10/L), mild-moderate thrombocytopenia (50 × 10/L ≤ PC < 100 × 10/L), and severe thrombocytopenia (PC < 50 × 10/L). We found that patients with severe thrombocytopenia had more blood transfusion, shorter days free from organ support, and worse outcomes as compared with the normal group. However, there was no significant difference between normal and mild-moderate thrombocytopenia groups. Furthermore, a subgroup analysis showed that rescue therapy with rhTPO could rapidly lead to a recovery of the PC, prolong days free from organ support, increase survival days, and reduce the 28-day mortality in sepsis patients with severe thrombocytopenia. These results suggested that sepsis patients with severe thrombocytopenia, not mild-moderate thrombocytopenia, had a poorer prognosis. RhTPO, probably as effective rescue therapy, could quickly recover PC and improve the prognosis in these sepsis patients.Copyright © 2020 Elsevier Ltd. All rights reserved.