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Introduction: Intravenous (i.v.) therapy may be associated with important catheter‐related morbidity and discomfort. The safety, efficacy, comfort, and cost‐effectiveness of peripherally inserted central catheters (PICCs) were compared to peripheral catheters (PCs) in a randomized controlled trial. Methods: Hospitalized patients requiring i.v. therapy ≥ five days were randomized 1:1 to PICC or PC. Outcomes were incidence of major complications, minor complications, efficacy of catheters, patient satisfaction, and cost‐effectiveness. Results: 60 patients were included. Major complications were observed in 22.6% of patients in the PICC group [six deep venous thrombosis (DVT), one insertion‐site infection] and 3.4% of patients in the PC group [one DVT; risk ratio (RR) 6.6; P = 0.03]. Superficial venous thrombosis (SVT) occurred in 29.0% of patients in the PICC group and 37.9% of patients in the PC group (RR 0.60 …