The intramuscular administration of penethamate hydriodide over 3 consecutive days and the intramammary administration of an ampicillin/cloxacillin combination were compared in lactating cows suffering from infectious clinical mastitis in one quarter, through an open, randomized, controlled multicenter field trial. Clinical examinations were carried out on d 1 (immediately before treatment), 3, 8, 17, and 22. Milk samples were taken from affected quarters for bacteriological analysis on d 1, 17, and 22, and from all quarters for somatic cell count (SCC) determination on d 1, 8, 17, and 22. There was no significant difference in bacteriological and clinical cure rates between the 2 treatment groups. The systemic treatment with penethamate resulted more frequently in a reduction of the milk SCC below the threshold of 250,000 cells/mL. This also occurred in the adjacent quarters not affected by clinical mastitis but with an SCC above 250,000 cells/mL before treatment. These findings suggest that the parenteral treatment with penethamate provides collateral cure on the quarters of the cows affected by subclinical mastitis. The number of quarters per cow affected by clinical or subclinical mastitis should be considered when selecting an antibiotic treatment by the local or systemic route.