Several investigators performing bone marrow transplantation studies have previously reported sporadic increases in mortality that were associated with pronounced swelling in the face, head and neck of mice. Over the past few years, we and others have noted an increasing number of experiments in which mice that have received total-body irradiation (TBI) or partial-body irradiation (PBI) develop swollen muzzles, drastic thickening of the upper lip and redness, bruising and/or swelling around the nose and muzzle and sometimes over the top of the head. We refer to this rapid and extreme swelling after irradiation as swollen muzzle syndrome (SMS). The development of SMS postirradiation is associated with morbidity that occurs earlier than would be expected from the traditional hematopoietic acute radiation syndrome (H-ARS), and has impeded studies in several laboratories attempting to evaluate medical countermeasures (MCM) against radiation. However, little has been done to characterize this somewhat unpredictable radiation effect. To investigate the cause and etiology of SMS, data from three different laboratories collected over a seven-year period from 100 MCM 30-day survival studies using mice from different vendors were retrospectively analyzed to determine the time of onset, progression and incidence of SMS in male and female mice exposed to various doses of ionizing radiation. An additional study compared incidence and etiology of SMS in mice from two different vendors (identified as vendors A and B) after exposure to the LD50/30 (X rays). Mice presenting with SMS, as well as non-SMS (irradiated) control mice, were necropsied to determine microbial status of the blood, heart, spleen, liver, kidney and muzzle tissue. Only mice from vendor A (20%) developed SMS. While the number of bacterial species isolated from various tissues of SMS and non-SMS mice was not different, the number of tissues positive for bacteria was significantly greater in SMS mice. At least one tissue in 83% of SMS mice from vendor A tested positive for Streptococcus agalactiae [group B beta Streptococcus (GBS)], compared to 25% of non-SMS mice from vendor A, and 0% of non-SMS mice from vendor B. In addition, all mice from vendor A with SMS had at least one tissue with >104 CFU/g, with GBS as the predominant bacterium, compared to only 25% of non-SMS mice from vendor A, and 0% of non-SMS mice from vendor B. The incidence and magnitude of GBS growth in cultures correlated with the onset of SMS; the earliest and heaviest infections occurred in mice presenting with SMS on days 5-6 postirradiation. The majority of SMS mice (5 out of 6) had positive blood cultures, with the same bacterial strain isolated from other tissues, suggesting systemic translocation via the bloodstream. We propose that testing of mice and the identification of the microorganisms frequently associated with SMS may provide guidance for selection of antimicrobials for use by other investigators in studies evaluating potential MCM, and for the ordering, handling and care of immunodeficient mice or mice that are to be rendered immunodeficient after acute irradiation.