To determine the effect of exogenous hyaluronic acid (HA) on healing of experimental wounds, responses in the hamster cheek pouch were measured after a hole was cut through the tissue with a biopsy punch. Fluorescence-labeled dextran was administered intravenously as a macromolecular tracer and the microcirculation was observed in vivo with a fluorescence microscope connected to a high-resolution television system. In one group a gelatin sponge soaked in 1.5 ml 16 mg/dl HA in water was applied topically at the time of injury and on postinjury days 1, 3, 5, and 7. The control group received the sponge soaked in the aqueous vehicle. Every 2 days after injury, the microcirculation was observed or histologic specimens were harvested. Wound size decreased almost twice as fast with HA compared with its vehicle (p less than 0.05). Healing was defined as time for total wound closure with at least one microvessel bridging the site of injury and required 16 or more days with vehicle but averaged less than 9 days with HA. Early during healing the repair site was surrounded by widespread extravasation of the fluorescent tracer, an index of inflammation; this area was reduced by two thirds 2 to 4 days after injury with HA compared with its vehicle (p less than 0.05). The density of perfused microvessels was twofold higher with HA 2 to 4 days after injury (p less than 0.05). However, microvessel density was similar in both groups by 6 days after injury and remained similar for at least 45 days after injury, which suggests that HA evoked no unusual angiogenic response. Histologic examination of fixed, stained specimens showed increases in intravascular leukocytes after injury and treatment-related differences in the distribution of intravascular leukocytes in 20 to 40 microns and 40 to 80 microns diameter microvessels 1 to 2 days after injury. Otherwise, leukocyte infiltration during healing was similar in both groups. The mechanism for the beneficial action of HA on healing is unknown. However, several in vitro studies suggest that HA is part of a feedback loop that promotes cell proliferation and migration in actively growing tissues. Alternatively, the role of HA in water homeostasis could favor tissue hydration, which has a well-known beneficial effect on healing.