Background: Patients with diffuse large B-cell lymphoma (DLBCL) with a high International Prognostic Index (IPI) are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy. This study aimed to compare the efficacy and safety of everolimus (EVE) v thalidomide (THA) as maintenance therapy in patients with DLBCL in complete remission and with a high risk of relapse after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Methods: This was a single-center, phase Ⅱ, randomized, open-label trial. Patients with stage II bulky or stage III to IV DLBCL, IPI ≥2, and a positron emission tomography/computed tomography-confirmed CR to first-line R-CHOP were randomized to receive EVE 5 mg/day for 1 year or THA 100 to 300 mg/day for 2 years or until disease relapse, unacceptable toxicity, or death. Eligible patients who refused any maintenance therapy were included as control group. Primary end point was disease-free survival (DFS). Results: A total of 102 patients were randomized to EVE (n = 50) or THA (n = 52). After a median follow-up of 34.2 months, 2-year DFS were 84.9% with EVE v 84.2% with THA (HR, 0.958; 95% CI, 0.370 to 2.484). 2-year overall survival (OS) were 93.4% with EVE v 91.4% with THA (HR, 0.711; 95% CI, 0.169 to 2.998). The control group included 137 patients, for whom 2-year DFS and OS was 62.4% and 81.6%, respectively. Both EVE and THA arms had a superior DFS (EVE v control, HR, 0.345; 95% CI, 0.165 to 0.722; THA v control, HR, 0.350; 95% CI, 0.174 to 0.706) and OS (EVE v control, HR, 0.216; 95% CI, 0.067 to 0.701; THA v control, HR, 0.335; 95% CI, 0.132 to 0.852) compared to control group. Grade 3 or 4 adverse events with EVE v THA were mucositis (8%), leukopenia (8%), thrombocytopenia (4%), infection (2%), and leukopenia (6%), thrombocytopenia (4%), infection (2%), respectively. Conclusions: The efficacy of everolimus and thalidomide as maintenance therapy was similar, both of which significantly improved DFS and OS in patients with high-risk DLBCL after achieving CR to R-CHOP. Everolimus administered 5 mg/day and thalidomide administered 100 to 300 mg/day were tolerated well.