: OBJECTIVES: Collagen accumulation in the sponge-induced granuloma is under inhibitory influence of melatonin. This effect was observed when the pineal hormone was injected late in the afternoon. DESIGN: The present study was conducted to compare the afternoon and morning melatonin application and to answer the question whether melatonin effect on the collagen accumulation in wounds is dependent on tissue circadian sensitivity to the pineal hormone. METHODS: In order to induce granulation tissue development, the Ivalon sponge was implanted subcutaneously in the Wistar rats. Then the animals were divided into 5 groups: intact controls, rats injected with vehicle in the morning or in the late afternoon, as well as animals receiving melatonin (30 &mgr;g/100g body wt) in the morning or late afternoon. After 4 weeks, the sponges were removed for the analysis of both soluble and total collagen content. Collagen was analyzed as hydroxyproline content in the tissue. Insoluble collagen was calculated. RESULTS: The afternoon application of melatonin was seen to decrease the total and insoluble collagen content in the sponge-induced granuloma (p<0.05). However, morning administration of the pineal hormone increased collagen capacity in the granulation tissue (p<0.01). CONCLUSION: Therefore, contradictory effect of morning or afternoon melatonin application on the collagen content in the granulation tissue has been shown. This phenomenon is supposed to be due to various circadian sensitivity of tissues to melatonin and may suggest that the mechanism of melatonin regulatory action on collagen accumulation in wounds is complex.