Mycobacterium senegalense is a Non-Tuberculous Mycobacterium (NTM) belonging to the M. fortuitum group, often associated with veterinary diseases, such as bovine farcy. However, it can also cause human infections and appears to be involved in Catheter-Associated Infections in immunocompromised patients. Here, we report the first Italian isolation of a strain of M. senegalense from a 16-year-old oncological female patient being treated at Fondazione IRCCS Policlinico San Matteo Pavia (Italy). Following pain at the Port-a-Cath site, a pus culture was collected and the positivity for the M. fortuitum group revealed the NTM infection. Antimicrobial susceptibility tests were performed and interpreted according to the available CLSI breakpoints. This information allowed us to implement the correct antibiotic therapy that, together with the device removal, led to the patient’s recovery. Finally, due to the increasing number of isolations, the possible presence of NTM infections in prosthetic devices should be among the primary diagnostic questions in a clinical setting.