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Selective mutism is a rare social anxiety disorder characterized by a total lack of speech in certain specific situations despite the ability to speak in others. Both genetic and psychosocial factors are thought to be involved in its presentation, persistence, and response to treatment. This case report describes a case of young female monozygotic twins who presented with selective mutism and their treatment spanning a 2-year period. It highlights the strong genetic association along with environmental factors such as social isolation and consequences of maternal social phobia, all contributing to treatment resistance, despite an intensive multimodal biopsychosocial approach. General issues related to the difficulties in treating monozygotic twins are also addressed.