Background: Primary pleural lymphoma is a rare disease posing diagnostic and therapeutic challenges. Case presentation: We present a 65-year-old woman with dyspnoea, cough, and asthenia, with no significant past medical history. Chest X-ray and computed tomography showed extensive right pleural effusion. Video-assisted thoracoscopy demonstrated multiple pleural nodules, while pleural fluid analysis revealed a lymphocytic exudate, and finally, a primary pleural lymphoma diagnosis was confirmed by immunohistochemistry analysis in pleural nodules biopsy. Discussion: In this regard, eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, dexamethasone, and rituximab were indicated, and after one year of follow-up, complete clinical and radiological remission was observed. Conlusions: We conclude that video-assisted thoracoscopy with an appropriate histopathological examination remains the gold standard for diagnosis, while R-CHOP chemotherapy plus rituximab may represent a highly effective therapeutic choice.