OBJECTIVES: Extended intramammary treatment of bovine clinical mastitis (CM) results in better cure rates but should be balanced economically against higher drug costs and extra waste of saleable milk because of a longer milk discard period. This study aimed to compare licensed extended treatment with pirlimycin (5 infusions q.d.) to shorter licensed treatments with cephapirin (2 infusions b.i.d.) and hetacillin (3 infusions q.d.) in dairy cows with CM caused by gram-positive pathogens (gram+CM), accounting for approximately 28% of all bovine mastitis cases in the US. METHODS: A decision tree was developed in MS Excel, considering first and recurrent CM episodes, culling and death of dairy cows with gram+CM over an entire lactation period of 305 days. The model considered costs and losses associated with CM and its treatment, culling or deaths as well as income generated from saleable milk production and sold cows. Prices and cost data were compiled from public sources (US-2010, perspective of the producer); efficacy data were derived from published studies.  All input parameters were varied extensively in one-way sensitivity analyses. RESULTS: Per treated cow, the income from milk production over one lactation period was $3051.72 (pirlimycin), $3054.66 (cephapirin), and $3049.21 (hetacillin). Costs associated with the disease and treatment totaled to $226.78 (pirlimycin), $236.84 (cephapirin), and $238.34 (hetacillin). As such, extended treatment with pirlimycin results in a higher profit margin of $7.12 and $14.07 per treated cow and per lactation, compared to 2 to 3 infusions with cephapirin and hetacillin, respectively. Fewer deaths or culling occurred with pirlimycin. Outcomes were most sensitive to cure rates of first mastitis episodes. CONCLUSIONS: With US 2010 cost/price data, the economic drawbacks of extended mastitis treatment were more than offset by better efficacy with 5-day pirlimycin treatment compared to 2 to 3 infusions with cephapirin or hetacillin.