Primary effusion lymphoma (PEL) is an HIV-associated B-cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV). There is no validated prognostic model in PEL, and prognosis is thought to be poor compared to other HIV-associated NHL. We derived the PEL-Prognostic score (PEL-PS) from an international real-world training set of 59 patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy from the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and the National Center for HIV Malignancy at the Chelsea and Westminster Hospital (CWH) in England from 2000 to 2022. We identified prognostic factors associated with overall survival (OS). In a multivariable Cox model, ECOG ≥ 3 (p = 0.007
hazard ratio [HR] = 4.0 [95% CI: 1.5-11.1]) and hemoglobin <
8 g/dL (p = 0.006
HR = 3.8 [95% CI: 1.5-9.7]) were jointly associated with lower survival probability. The resulting PEL-PS separated patients with no negative prognostic factors (score 0: hemoglobin ≥ 8 g/dL and ECOG ≤ 2, 48.1% of patients) with median OS of 10.6 years versus patients with 1-2 negative prognostic factors (score 1-2: hemoglobin <
8 g/dL and/or ECOG ≥ 3, 51.9% of patients) with median OS of 0.8 years (p <
0.0001). The PEL-PS was then validated in 58 patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at Hôpital Saint-Louis in France over the same period: median OS in patients with PEL-PS 0 was 16.9 years versus 0.6 years in patients with PEL-PS score of 1-2 (p <
0.0001). The PEL-PS identifies patients with good and poor prognosis. Patients with poor prognosis may benefit from novel therapies.