Capillary leak syndrome (CLS) is characterized by plasma extravasation into the interstitium with resultant hypotension, anasarca, hemoconcentration, and hypoalbuminemia in the absence of albuminuria. Initially reported in Clarkson's disease (systemic capillary leak syndrome), CLS has been observed in multiple disease settings, the most common being sepsis. In oncology, CLS has been reported more often as a complication from therapy, and less often from malignancy. In this case study, we documented clinical manifestation, laboratory features, and radiological findings of CLS from rituximab therapy when employed in combination with a multi-agent chemotherapy regimen (EPOCH-R). Differentiating drug-induced CLS from sepsis, which presents with the same clinical features, is important in avoiding further exposure to rituximab, which could be fatal to the patient.