This is a case of a woman with breast cancer, who developed mediastinal sarcoid-like reaction, depicted on PET/CT, which was histologically confirmed, following treatment with trastuzumab and pertuzumab. The development of noncaseating granulomas in patients who do not fulfill the criteria for systemic sarcoidosis is known as sarcoid-like reaction, having been described in association with trastuzumab in a few case reports, but none with pertuzumab. Physicians should be aware of the potentially higher rate of sarcoid-like reaction in patients receiving HER-2 treatment. The symmetric pattern of mediastinal lymphadenopathy, although indicative, is not pathognomonic for sarcoid-like reaction, and biopsy is necessary to exclude disease progression.