Vaccination is a desirable emerging strategy to combat poultry red mite (PRM), Dermanyssus gallinae. We performed trials, in laying hens in a commercial-style cage facility, to test the vaccine efficacy of a native preparation of soluble mite extract (SME) and of a recombinant antigen cocktail vaccine containing bacterially-expressed versions of the immunogenic SME proteins Deg-SRP-1, Deg-VIT-1 and Deg-PUF-1. Hens (n=384 per group) were injected with either vaccine or adjuvant only (control group) at 12 and 17 weeks of age and then challenged with PRM 10days later. PRM counts were monitored and, at the termination of the challenge period (17 weeks post challenge), average PRM counts in cages containing birds vaccinated with SME were reduced by 78% (p<0.001), compared with those in the adjuvant-only control group. When the trial was repeated using the recombinant antigen cocktail vaccine, no statistically significant differences in mean PRM numbers were observed in cages containing vaccinated or adjuvant-only immunised birds. The roles of antigen-specific antibody levels and duration in providing vaccine-induced and exposure-related protective immunity are discussed.