Background A number of antimicrobial-impregnated discs to prevent central-line-associated bloodstream infection (CLABSI) are marketed but it is unclear which disc is most effective. Aim To investigate the feasibility and safety of comparing two antimicrobial-impregnated discs to prevent CLABSI. Methods A single-centre, parallel group, randomized controlled trial was conducted in a 929-bed tertiary referral hospital. Hospital inpatients requiring a peripherally inserted central catheter were randomized to chlorhexidine gluconate (CHG) or polyhexamethylene biguanide (PHMB) disc dressing group. Dressings were replaced every seven days, or earlier, if clinically required. Participants were followed until device removal or hospital discharge. Feasibility outcomes included: proportion of potentially eligible participants who were enrolled; proportion of protocol violations; and proportion of patients lost to follow-up. Clinical outcomes were: CLABSI incidence, diagnosed by a blinded infection control practitioner; all-cause bloodstream infection (BSI); and product-related adverse events. Findings Of 143 patients screened, 101 (71%) were eligible. Five (3.5%) declined participation. There was one post-randomization exclusion. Two (2%) protocol violations occurred in the CHG group. No patients were lost to follow-up. Three (3%) BSIs occurred; two (2%) were confirmed CLABSIs (one in each group) and one a mucosal barrier injury-related BSI. A total of 1217 device-days were studied, resulting in 1.64 CLABSIs per 1000 catheter-days. One (1%) disc-related adverse event occurred in the CHG group. Conclusion Disc dressings containing PHMB are safe to use for infection prevention at catheter insertion sites. An adequately powered trial to compare PHMB and CHG discs is feasible.