Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity. Case Presentation: We report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5- fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC. Results: In both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations. Conclusion: We reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.