Most previous animal studies reporting improved epithelialisation and healing of burn wounds under hyperbaric oxygen (HBO) did not include the conventional treatment with topical antibiotics as part of the protocol, and did not compare the effectiveness of HBO therapy with that of normobaric 100% oxygen (NO). The purpose of our study was to compare the results of combined treatment with HBO + silver sulfadiazine (SS) and those of treatment with NO + SS or SS alone. Deep second degree burns were produced on the depilated backs of 54 guinea pigs using a validated burn protocol. The animals were assigned to three treatment groups: HBO + SS, NO + SS, and SS. Dressings were changed daily. HBO was administered at 2 atmospheres absolute (ATA) for 90 min BID, and NO for 90 min BID. The parameters compared among the groups were laser Doppler flowmetry, and burn wound contracture and re-epithelialisation data derived from computerised planimetry of photographs of the wound. No differences in laser Doppler flowmetry results or the magnitude of contracture were found between the groups. Significantly increased re-epithelialisation was observed under NO + SS starting 10 days after the burn (P = 0.02, ANOVA). This significance stems from the difference between the HBO + SS and NO + SS groups (Tukey test). These data indicate that excessively high levels of tissue PO2 might compromise burn healing, and explain our results. A further study comparing combined treatment using a milder HBO protocol + SS and NO + SS is indicated in the search for the optimal HBO regimen.