Immune-related adverse events including cardiac toxicity are increasingly described in patients receiving immune checkpoint inhibitors. We described a malignant pericardial effusion complicated by a cardiac tamponade in an advanced non-small cell lung cancer patient who had received five infusions of atezolizumab, a PDL-1 monoclonal antibody, in combination with cabozantinib. The definitive diagnosis was quickly made by cytology examination showing typical cell abnormalities and high fluorescence cell information provided by the hematology analyzer. The administration of atezolizumab and cabozantinib was temporarily discontinued due to cardiogenic hepatic failure following cardiac tamponade. After the re-initiation of the treatment, pericardial effusion relapsed. In this patient, the analysis of the pericardial fluid led to the final diagnosis of pericardial tumor progression. This was afterwards confirmed by the finding of proliferating intrapericardial tissue by computed tomography scan and ultrasound. This report emphasizes the value of cytology analysis performed in a hematology laboratory as an accurate and immediate tool for malignancy detection in pericardial effusions.