This study was performed to investigate whether an intravenous (IV) strategy based on newgeneration midline catheters is an efficacious alternative to a conventional IV strategy consisting of peripheral venous catheters and central venous catheters, for patients needing IV therapy exceeding 5 days. Methods: This was a prospective, randomized, controlled study. Patients requiring more than 5 days of IV treatment were randomized to either a midline catheter-based IV strategy or a conventional strategy. The primary endpoint was the composite of the insertion of a central venous catheter (CVC) or the need for four or more peripheral venous catheter (PVC) insertions. The secondary outcomes included catheter dwell times and reasons for premature removal. Results: One hundred and twenty patients were included. The fraction of patients receiving four or more PVCs or having a CVC inserted was 12/58 (21%) in the midline group versus 38/58 (66%) in the conventional group (p < 0.001); the number needed to treat was 2.2. The median overall catheter dwell time was 7 days (range 0-60 days) in the midline group and 4 days (range 0-84 days) in the conventional group (p = 0.002). Conclusion:In patients requiring more than 5 days of IV therapy, a midline catheter strategy reduced the need for insertion of a CVC or four or more PVCs.