Treating and Preventing mastitis employing cationic steroidal antimicrobials (CSAs). Treating or preventing clinical mastitis in a mammal includes administering a cationic steroidal anti-microbial compound (CSA) formulation to the intra-mammary organ of a mammal (e.g., a dairy cow), such as by injection into the mammary organ (e.g., through the teat of the mammary organ), and/or topical application. The dairy cow can be lactating and have a somatic cell count (SCC) less than or equal to 500,000 cells/mL at the time of administering the CSA formulation. Alternatively, the dairy cow can be lactating and have a somatic cell count (SCC) greater than 500,000 cells/mL at the time of administering the CSA formulation. The dairy cow can be taken out of production during the administration of the CSA formulation for a period of time of about 3 days or less, 2 days or less, or 1 day or less.