Background: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a pathologic immune activation syndrome characterized by immune-mediated multiple organ system damage. Pleural effusion can occur as a specific manifestation of sHLH, however, has rarely been evaluated. This study aimed to describe the clinical characteristics of pleural effusion in sHLH and assesse whether it affects prognosis.Methods: We retrospectively analysed 203 newly diagnosed sHLH patients from July 2015 to July 2019 according to the HLH-2004 protocol. Baseline characteristics, laboratory results, and imaging materials were reviewedResults: Pleural effusion was found in 58.6% of the studied sHLH population, and imaging findings were characterized by minimal amounts and bilaterality. Multivariate analyses showed that sCD25 level and PLT ≤65×109/L were significant risk factors for developing pleural effusion in sHLH. Regarding prognostic value, survival analysis showed a lower survival probability for patients with pleural effusion than for those without pleural effusion (median OS, 90 vs. 164 days, p = 0.028). In the multivariate analysis, pleural effusion was an independent prognostic factor for OS (HR = 2.68; 95% CI 1.18–6.11, p = 0.019). Conclusions: Pleural effusion is frequently found in patients with sHLH and is associated with a higher inflammatory state and worse outcomes.