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Castellaniella defragrans is an environmental Gram-negative, non-fermenting β-proteobacterium that is not known as a human pathogen. Here, we report the first documented case of C. defragrans bacteraemia in an 82-year-old man with monoclonal B-cell lymphocytosis, subsequently diagnosed with chronic lymphocytic leukaemia, who presented with fever, confusion and clinical signs of sepsis. Blood cultures showed sustained growth of C. defragrans for 7 days. Imaging revealed pulmonary consolidations and mediastinal infiltration suggestive of mediastinitis. Further investigations did not identify a clear additional infectious focus. In addition, an immunological evaluation revealed severe cellular and humoral immunosuppression. Antimicrobial therapy with high-dose meropenem led to bacteraemia clearance and progressive clinical improvement. Treatment was completed with oral sulfamethoxazole-trimethoprim for a total of five weeks. This case highlights the potential of environmental microorganisms to cause severe infections in immunocompromised hosts.