Abstract Background and Aims aHUS is associated with dysregulation of the alternative complement pathway. C5 inhibitors (C5i) improve TMA response and renal recovery, but significant morbidity may remain. Although C5i studies have reported on TMA response rates after treatment discontinuation, TMA response data during index hospitalisation are limited. This study described TMA response during index aHUS hospitalisation using real-world evidence from a large, diverse cohort of presumed incident aHUS in the United States (US). Methods This was a retrospective cohort study of hospitalised adult patients with presumed aHUS with electronic healthcare records in the US Premier Healthcare Database, which contains ∼25% of all US hospitalisations (January 1, 2011–June 30, 2021). aHUS was defined as the presence of an International Classification of Diseases (ICD)-9-CM/ICD-10-CM diagnostic code for TMA or haemolytic uremic syndrome (HUS) and a treatment code for a C5i, without a diagnostic code for secondary causes of TMA/HUS or other C5i indications. Complete TMA response was defined by >25% decline of serum creatinine (SCr) and normalisation of platelets and lactate dehydrogenase (LDH) from index presentation, without renal replacement therapy (RRT) at discharge. Included patients had longitudinal laboratory data; patients with in-hospital death were excluded. Patient demographics, clinical characteristics, treatment patterns, and clinical outcomes were assessed as risk factors. Variables were analysed by Wilcoxon signed-rank test, Kruskal–Wallis test, Fisher's exact test, or Chi-square test, as appropriate. Results Of 634 adult patients hospitalised with presumed aHUS, 556 survived to discharge. SCr, platelet, LDH, and all three TMA response criteria data were available for 21.0% (117/556), 18.9% (105/556), 18.2% (101/556), and 16.5% (92/556) of patients, respectively. Median duration between the first and last laboratory measurement before discharge was 21 days (interquartile range [IQR]: 12–33) for SCr, 21 days (IQR: 14–32) for platelets, and 17.5 days (IQR: 11–27) for LDH. Only 6.5% (6/92) of patients achieved a complete TMA response at discharge, preventing statistical analysis with other parameters. Platelet normalisation occurred in 53.3% (56/105) of patients and was associated with younger median age (39 vs 54 years; P = 0.0167) and median time from admission to C5i (8 vs 10 days; P = 0.0459). LDH normalisation occurred in 29.7% (30/101) and was associated with male sex (60.0% vs 22.5%; P = 0.0005), Hispanic ethnicity (20.0% vs 7.0%; P = 0.0330), and median duration of intensive care unit stay (3.5 vs 8 days; P = 0.0185). A drop of >25% in SCr from admission to discharge occurred in 20.5% (24/117) and was associated with Hispanic ethnicity (16.7% vs 8.6%; P = 0.0089) and no RRT (45.8% vs 14.0%; P = 0.0014). Among patients with mortality data, the association between platelet normalisation and 60-day post-discharge mortality was significant (P = 0.0499). LDH normalisation and a >25% decline in SCr were not associated with 60-day (P = 0.6368 and P = 1.000, respectively) or 365-day (P = 0.4288 and P = 0.7023, respectively) post-discharge mortality. Conclusions In this US population of hospitalised adults with presumed incident aHUS, few patients achieved a complete TMA response at discharge, despite C5i. Small sample size limited assessment of clinical characteristics associated with complete TMA response; however, achievement of each TMA response criterion was associated with unique clinical and patient characteristics. Future efforts should focus on characterising patients with aHUS at high risk at discharge and on developing novel precision therapies to improve outcomes.