Multiple sclerosis (MS) patients may experience severe local inflammatory skin reactions during disease-modifying therapy with subcutaneously injected interferon-β (IFN-β). It is common clinical practice to switch those patients to an intramuscularly administered formulation, where severe local skin reactions have not been described. Here we report a 42-year-old woman with stable relapsing–remitting MS, who was switched from subcutaneously to intramuscularly injected IFN-β1a due to abdominal skin necroses and slight multifocal lipoatrophy. After two years of complication-free therapy with intramuscular IFN-β1a, the patient slowly developed painful lobular panniculitis and severe lipoatrophy of both lateral thighs. A careful diagnostic workup identified misguided subcutaneous injections due to a wrong injection angle as the most plausible cause. Upon correction of her injection technique, pain and skin reddening resolved, while her disfiguring lipoatrophy was irreversible. This report should enhance awareness that severe skin adverse effects may also occur, although rarely, with IFN-β for intramuscular injection. Early recognition and correction of the injection technique may help to prevent severe complications.