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 >or= 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; P = 0.20). Patients in the PICC group required 1.16 catheters on average during the study period, compared with 1.97 in the PC group (P < 0.04). The mean number of venipunctures (catheter insertion and blood sampling) was 1.36 in the PICC group vs. 8.25 in the PC group (P < 0.001). Intravenous drug administration was considered very or quite satisfying by 96.8% of the patients in the PICC group, and 79.3% in the PC group. Insertion and maintenance mean cost was 690 US$ for PICC and 237 US$ for PC. DISCUSSION: PICC is efficient and satisfying for hospitalized patients requiring i.v. therapy >or= five days. However, the risk of DVT, mostly asymptomatic, appears higher than previously reported, and should be considered before using a PICC.