Rothia dentocariosa, a commensal organism of the oral cavity, is an uncommon pathogen that predominantly affects immunocompromised individuals or patients with indwelling medical devices. The paper reports a case of Rothia dentocariosa catheter-related bloodstream infection in an 18-month-old girl with Pompe disease and severe hypertrophic cardiomyopathy. The patient, who was receiving weekly enzyme replacement therapy via a central venous catheter, developed fever during catheter use. Blood cultures obtained from the catheter yielded Rothia dentocariosa. In light of the patient’s stable clinical condition and the high risks associated with catheter replacement, a conservative therapeutic approach was adopted. Targeted antimicrobial therapy with daptomycin and amoxicillin/sulbactam, guided by susceptibility testing, successfully eradicated the infection without catheter removal. At one-month follow-up, the patient remained afebrile and free of recurrence. This case underscores the feasibility of conservative management of Rothia dentocariosa catheter-related infections in selected clinical settings and highlights the need for individualized therapeutic decision-making.