COVID-19 presents with a wide spectrum of clinical and radiological manifestations, including pleural effusion. The prevalence and prognostic impact of pleural effusion are still not entirely clear. This is a retrospective, single-center study including a population of consecutive patients admitted to the University Hospital of Cisanello (Pisa) from March 2020 to January 2021 with a positive SARS-CoV-2 nasopharyngeal swab and SARS-CoV-2-related pneumonia. The patients were divided into two populations based on the presence ( = 150) or absence ( = 515) of pleural effusion on chest CT scan, excluding patients with pre-existing pleural effusion. We collected laboratory data (hemoglobin, leukocytes, platelets, C-reactive protein, procalcitonin), worst PaO /FiO ratio as an index of respiratory gas exchange impairment, the extent of interstitial involvement related to SARS-CoV-2 pneumonia and data on intensity of care, length of stay and outcome (discharge or death). The prevalence of pleural effusion was 23%. Patients with pleural effusion showed worse gas exchange ( < 0.001), longer average hospital stay ( < 0.001), need for more health care resources ( < 0.001) and higher mortality ( < 0.001) compared to patients without pleural effusion. By multivariate analysis, pleural effusion was found to be an independent negative prognostic factor compared with other variables such as increased C-reactive protein, greater extent of pneumonia and older age. Pleural effusion was present at the first CT scan in most patients (68%). Pleural effusion associated with SARS-CoV-2 pneumonia is a relatively frequent finding that is confirmed to be a negative prognostic factor. Identifying early prognostic factors in an endemic-prone disease such as COVID-19 is necessary to optimize its clinical management. Further clinical studies aimed at better characterizing pleural effusion in these patients will be appropriate in order to clarify its pathogenetic role.