Background: Despite improved prognosis, patients with transfusion-dependent β-thal commonly experience treatment and disease complications. Aims: To assess the prevalence and severity of treatment and disease complications, capture disease management, and identify predictors of complications in a representative sample of patients with transfusion-dependent β-thal in routine settings in Greece. Methods: ULYSSES is an epidemiological, multicenter, retrospective cross-sectional study of adults diagnosed with β-thal ≥12 months before enrollment who received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion-free period ≥35 days in the 24 weeks before enrollment. Hemoglobinopathies S/β- and α-thalassemia were excluded. Primary data were collected at a single visit and through chart review. Results: From Oct 21, 2019 to June 15, 2020, a total of 201 eligible patients were enrolled by 12 major thalassemia centers; 64.2% were female, median age was 45.7 years (interquartile range [IQR], 40.2–50.5; 75.6% >40 years), mean (standard deviation [SD]) time since diagnosis was 42.9 (7.8) years.Overall, 44.3% were β+β+, 36.8% β+β0, 13.4% β0β0, and 5.5% carried β+, δβ-Sicilian, Corfu δ0β+, Turkish (δβ)0, and hemoglobin Lepore combinations. The most common β-globin mutations were IVS1-nt110 G>A (63.7%), Codon 39 C>T (25.4%), and IVS1-nt6 T>C (22.9%). Median (IQR) age at diagnosis and RBC transfusion initiation was 0.8 (0.4–2.8) and 1.3 (1.0–5.0) years, respectively. During the 48 weeks prior to enrollment, patients received a mean (SD) of 34.2 (9.5) RBC units from a median (IQR) of 23.0 (18.0–28.0) RBC transfusion events. Before enrollment, all patients had received iron chelation therapy (ICT), started at a median (IQR) age of 6.4 (3.2–12.9) years (median [IQR] exposure 35.6 [30.0–40.0] years), and 53.2% had received other therapies, including folic acid (48.3%); 53.2% had a splenectomy at a median (IQR) age of 22.0 (14.0–29.0) years. From diagnosis to enrollment, patients developed 1443 cumulative complications (median 6 [range, 1–55]; 585 ongoing at enrollment; 19.6% [237/1211] known Grade ≥3). Disease-related complications related to β-thal were experienced by all patients (total 1089 [median 5 (range, 1–21)]; 22.1% were Grade ≥3). Over half of patients (53.2%) experienced complications related to treatment (total 354; [median 1 (range, 0–35)]; 13.0% Grade ≥3; Figure), of which 43.4% (n=273), 25.4% (n=73), and 2.0% (n=8) were related to RBC transfusions, ICT, or other treatments, respectively. Of patients 18–40 years, 36.7%, 30.6%, and 16.3% experienced ≥1 treatment-related, RBC transfusion,or ICT complication, respectively, compared with 58.6%, 48.7%, and 28.3% of those >40 years. The 48-week pre-enrollment hospitalization rate due to disease or treatment complications was 0.076 per patient-year (95% confidence interval [CI], 0.045–0.128). Medical/surgical history (odds ratio[OR], 5.16; 95% CI, 1.91–13.92; P=0.001), splenectomy (OR, 2.86; 95% CI, 1.16–7.02; P=0.022), and >24 transfusion events in 48 weeks prior to enrollment (OR, 2.78; 95% CI, 1.15–6.74; P=0.023) were associated with increased odds for developing treatment-related complications. In contrast, splenectomy was associated with lower odds (OR, 0.27; 95% CI, 0.08–0.89; P=0.031) of having either treatment- or disease-related complications. Image:Summary/Conclusion: Real-world data generated by ULYSSES underscore the substantial complication burden of patients with transfusion-dependent β-thal routinely managed in Greece, which worsens with advanced age. †First and second author have contributed equally.