We previously reported that the area under the curve of log-transformed cytomegalovirus antigenemia (CMV-AUC) until 100 days after allogeneic hematopoietic cell transplantation (allo-HCT) was associated with an increased risk of non-relapse mortality. We applied a risk-adapted letermovir (LTV) prophylaxis strategy guided by a risk score that predicts a higher CMV-AUC. First, we retrospectively analyzed 278 allo-HCT recipients between 2007 and 2017 (Period 1). We scored risk factors for higher CMV-AUC by odds ratios: malignant lymphoma including adult T cell leukemia/lymphoma (1 point), an unrelated or haploidentical donor (1 point), and recipient/donor CMV serostatus (+/+
2 points, +/-
3 points). We have administered LTV to patients with a total score of ≥ 4 points. We then focused on 143 patients who underwent allo-HCT when we applied this strategy (Period 2). Forty patients (28%) in Period 2 received LTV prophylaxis. Two patients (5.4%) exhibited higher CMV-AUC among 37 patients in the higher-risk group (≥ 4 points). However, as many as 33% of the patients with 3 points in Period 2 experienced higher CMV-AUC. Notably, in the lower-risk patients of Period 2, 68% of patients who received systemic steroids for acute graft-versus-host-disease (GVHD) developed higher CMV-AUC. Our risk-adapted LTV prophylaxis strategy effectively prevented higher CMV-AUC in the higher-risk group and reduced the use of LTV. Additionally, including the use of systemic steroids for acute GVHD in this risk-adapted approach is preferable.