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Biofilms pose a unique therapeutic challenge because of the antibiotic tolerance of constituent bacteria. Treatments for biofilm-based infections represent a major unmet medical need, requiring novel agents to eradicate mature biofilms. Our objective was to evaluate bacteriophage lysin CF-301 as a new agent to target <i>Staphylococcus aureus</i> biofilms. We used minimum biofilm-eradicating concentration (MBEC) assays on 95 <i>S. aureus</i> strains to obtain a 90% MBEC (MBEC<sub>90</sub>) value of ≤0.25 μg/ml for CF-301. Mature biofilms of coagulase-negative staphylococci, <i>Streptococcus pyogenes</i>, and <i>Streptococcus agalactiae</i> were also sensitive to disruption, with MBEC<sub>90</sub> values ranging from 0.25 to 8 μg/ml. The potency of CF-301 was demonstrated against <i>S. aureus</i> biofilms formed on polystyrene, glass, surgical mesh, and catheters. In catheters, CF-301 removed all biofilm within 1 h and killed all released bacteria by 6 h. Mixed-species biofilms, formed by <i>S. aureus</i> and <i>Staphylococcus epidermidis</i> on several surfaces, were removed by CF-301, as were <i>S. aureus</i> biofilms either enriched for small-colony variants (SCVs) or grown in human synovial fluid. The antibacterial activity of CF-301 was further demonstrated against <i>S. aureus</i> persister cells in exponential-phase and stationary-phase populations. Finally, the antibiofilm activity of CF-301 was greatly improved in combinations with the cell wall hydrolase lysostaphin when tested against a range of <i>S. aureus</i> strains. In all, the data show that CF-301 is highly effective at disrupting biofilms and killing biofilm bacteria, and, as such, it may be an efficient new agent for treating staphylococcal infections with a biofilm component.