Background: Rising cancer incidence and mortality have increased the use of central venous catheters (CVCs), including peripherally inserted central catheters (PICCs) and port-a-cath systems (PCSs), which play an important role in treatment administration. However, CVCs are associated with mechanical, infectious, and thrombotic complications. This study evaluates PCS-related complications and their management in oncological patients at The Oncology Institute “Prof. Dr. Ion Chiricuță,” Cluj-Napoca, Romania. Methods: This non-randomized, observational, retrospective study included cancer patients who had a PCS implanted at The Oncology Institute “Prof. Dr. Ion Chiricuță,” Cluj-Napoca, between 1 January 2024 and 31 December 2024 and were enrolled in a follow-up protocol to monitor and manage PCS-related complications. This study evaluated the incidence of complications, their association with predefined prognostic factors, and their management. Results: In the study cohort (n = 124 patients), complications related to the PCS were observed in 20% of the patients, with a mean interval to complication onset of 47 days. Early-onset complications were observed in 40% of patients, while the remaining 60% developed late-onset complications. PCS infection was the most common complication (10 patients), followed by wound dehiscence and thrombosis (6 patients each). Bleeding, extravasation, catheter migration, port malfunction, and torsion were each documented in a single patient. No prognostic factors were significantly associated with early or late PCS complications, with thrombosis approaching significance (p = 0.051). Conclusions: PCSs are generally safe in oncology patients; infections and thrombosis predominate as PCS-related complications, but rarely require removal, and standardized care enables long-term use, improving patient quality of life.