Human loxoscelism was modeled in albino rabbits by injection of brown recluse spider (Loxosceles reclusa) venom, and the effects of daily or twice-daily hyperbaric oxygen treatment on wound healing were investigated. Lesions similar to those seen in humans were produced in rabbits by intradermal injection of 200 microliters of a venom extract (0.21 microgram protein per microliter), including edema and erythema, ischemia and cyanosis in the first 12 hr, extensive purpura by 24 hr, and crateriform ulcer formation by day four, with induration and eschar formation. Hyperbaric oxygen treatments, consisting of two atmospheres absolute (2 ATA) for 60 min, were applied daily (n = 8) or twice daily (n = 8), while control animals (n = 8) received no treatment. Treatments were initiated 72 hr after venom injection (day 3) to duplicate typical clinical treatment delays, and were administered for seven consecutive days. No significant effects of hyperbaric oxygen treatment on lesion healing were seen as measured by lesion area. However, histologic evaluation of wound tissue collected at euthanasia on day 24 showed clear differences between rabbits receiving twice-daily treatments and those receiving daily or no treatment. The former showed complete re-epithelization or slight ulceration, while the latter usually had necrotic cavities extending into the dermis, with myonecrosis and inflammatory cell accumulation. Thus, no superficial differences were seen between groups, but twice-daily treatments resulted in enhanced recovery at the histologic level.