Objective: To reveal the expression and clinicopathological significance of topoisomerases type IIα (TOP2A) and programmed cell death-ligand 1 (PD-L1) in systemic anaplastic large cell lymphoma (sALCL). Methods: Forty-four patients with sALCL diagnosed from March 2010 to June 2022 at Fujian Cancer Hospital were selected for the detection of TOP2A and PD-L1 by immunohistochemistry. Follow-up using telephone interview was conducted to detect the survival of patients up to April 15, 2022. Results: Of the 44 sALCL patients, 32 were males, 12 were females, with a median age 51 years (ranging from 12 to 78 years). All 44 cases were divided into 2 types according to the World Health Organization (WHO) classification, namely, anaplastic lymphoma kinase (ALK) positive ALAL (n=17) and ALK negative ALCL (n=27). The positive rates of TOP2A and PD-L1 were 60.5% (26/43) and 47.4% (18/38), respectively. According to the result of Spearman correlation analysis, the expression of TOP2A protein was associated with that of PD-L1 protein in sALCL. In addition, the follow-up time ranged from 1 to 137 months. As reveal by Kaplan-Meier survival analysis, the prognosis of patients was related to TOP2A (P=0.017), PD-L1 (P=0.025), lactic dehydrogenase (LDH) (P=0.004) and hepatosplenomegaly (P=0.045). Conclusion: The expression of TOP2A protein is associated with that of PD-L1 in sALCL, and that the negative expression of TOP2A and PD-L1 protein is better than that of patients with positive expression, which can be served as an effective prognostic biomarker of sALCL.