One objective of this field investigation was to evaluate the efficacy of extended therapy with pirlimycin hydrochloride with or without vaccination prior and during therapy for S. aureus mastitis. 80% of cows and 44% of quarters were infected with S. aureus. S. aureus infected animals were split into 3 groups with all quarters of all cows treated with extended pirlimycin therapy. One group received a vaccine which had herd autogenous strains (AV), and another group received a new trivalent S. aureus vaccine (TV) at 14 and 1.5 days prior to treatment, and 6 days after treatment started. Cure rates at 32 days post treatment were 18%, 38%, and 56% for treatment only (TO), (AV), and (TV) groups. Cure rates at 60 days post treatment were 14%, 33%, and 33%, respectively when all cows were included in the analysis, and 14, 17, and 14%, respectively, when high SCC quarters with no 60 day data were excluded from the analysis. Coupling vaccination to extended therapy was not successful in this herd ( compared to other data) possibly due to underlying herd nutrition problems. This study also points out that bacteriological cure must be assessed later (>30–45 days post treatment) and/or quarter SCC should be used when multiple therapy strategies are coupled together.