Background: Peripherally inserted central catheters (PICCs) are commonly used for delivering intravenous therapy. PICC failure is unacceptably high (up to 40%) due to mechanical, infectious and thrombotic complications. Poor securement potentiates all complication types. This randomised controlled trial (RCT) aimed to examine the feasibility of a large RCT of four dressing and securement methods to prevent PICC failure. Methods: This single-centre pilot RCT included 124 admitted medical/surgical/cancer patients aged≥16years with a PICC. Interventions were: (i) standard polyurethane dressing and sutureless securement device (SPU+SSD, control); (ii) polyurethane with absorbent lattice pad dressing (PAL+Tape); (iii) combination securement-dressing (CSD); and (iv) tissue adhesive (TA+SPU). All groups except TA+SPU had a chlorhexidine-gluconate (CHG) impregnated disc. Feasibility outcomes were recruitment and safety/acceptability of the interventions. The primary outcome was PICC failure, a composite of PICC removal for local infection, catheter-associated bloodstream infection, dislodgement, occlusion, and/or catheter fracture. Secondary outcomes included individual complications, dressing failure and dwell time, PICC dwell time, skin complications/phlebitis indicators, product costs, and patient and staff satisfaction. Qualitative feedback was also collected. Results: PICC failure incidence was: PAL+CHG+Tape (1/5; 20%; 17.4/1000days), SPU+SSD+CHG (control) (4/39; 10%; 9.0/1000days), TA+SPU (3/35; 9%; 9.6/1000days), and CSD+CHG (3/42; 7%; 9.4/1000days). Recruitment to PAL+CHG+Tape was ceased after five participants due to concerns of PICC dislodgement when removing the dressing. CSD+CHG, TA+SPU (TA applied onlyat PICCinsertion time), and control treatments were acceptable to patients and health professionals. Conclusion: A large RCT of CSD+CHG and TA+SPU (but not PAL+CHG+Tape) versus standard care is feasible. Trial registration: Australian and New Zealand Clinical Trials Registry, ACTRN12616000027415. Registered on 15 January 2016.