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Trastuzumab and pertuzumab are monoclonal antibodies widely used in the treatment of HER2-positive breast cancer. Although well tolerated in most cases, they can nevertheless cause severe hypersensitivity reactions, which are rare but potentially fatal. We report the case of a 40-year-old female patient being treated for HER2-positive breast cancer who developed anaphylactic shock immediately after subcutaneous administration of trastuzumab (Herceptin SC) at the start of an intravenous infusion of pertuzumab (Perjeta). The patient presented with sudden dyspnoea, hypotension, generalized urticaria, tachycardia, and malaise with altered consciousness. Emergency treatment consisted of discontinuing the drugs, intramuscular administration of adrenaline, oxygen therapy, and intravenous rehydration. Tryptase levels confirmed the diagnosis of anaphylactic shock. Trastuzumab SC, which contains recombinant hyaluronidase, an excipient sometimes implicated in allergic reactions, is the main suspect in this case. The literature reports an incidence of severe hypersensitivity of less than 1% with trastuzumab SC and around 0.7% for pertuzumab IV. The reaction could be mediated by an IgE-dependent mechanism. Treatment involves immediate management of the shock and, if further therapy is required, implementation of a desensitization protocol under specialist supervision. This case highlights the importance of vigilance regarding these rare adverse effects, staff training in the management of anaphylaxis, and the immediate availability of adrenaline in hospitals.