Mycobacterium ulcerans causes chronic nectotizing ulcers of the skin and subcutaneous tissue and is a serious health problem in some tropical countries. Chemotherapy has not been effective, and the treatment of choice is extensive debridement followed by skin grafting. In spite of this, many infections are complicated by disfiguring scars, contraction deformities, and--rarely--amputation. There are other procedures that may promote healing (e.g., heat treatment, rifampicin), but none has been completely evaluated. In our study, hyperbaric oxygenation (HBO), an effective treatment for many bacterial diseases, including some mycobacterial infections, was used to treat mice with M. ulcerans-infected footpads. Three groups (40 mice/group) were treated daily with 100% oxygen by three different protocols: 2.5 ATA for 2 h; 2.5 ATA for 1.25 h, twice a day; and 2 ATA for 3.5 h. The degree of infection in the treated mice was compared weekly with 40 positive controls (infected, not treated). The HBO therapy was more effective in the group treated at 2.5 ATA for 1.25 h, twice a day. After 25 weeks, there had been two feet autoamputated and only 12 deaths among the mice, as compared to 18 feet amputated and 24 deaths in the control group. Thus, hyperbaric oxygenation has a beneficial effect in mice and, if used in conjunction with other therapeutic procedures in man, may be an effective therapeutic adjunct in treating M. ulcerans infections.