A clinical trial was designed to evaluate the effects of topical application of melatonin on the crevicular fluid levels of interleukins and prostaglandins and to evaluate changes in clinical parameters. A consecutive sample of 90 patients were recruited from the Health Centre of Pinos Puente in Granada, Spain and divided into 3 groups: 30 patients with diabetes and periodontal disease, who were given melatonin; 30 patients with diabetes and periodontal disease, who were given a placebo, and 30 healthy individuals with no history of systemic disease or clinical signs of periodontal disease, who were also given a placebo. The 30 patients with diabetes and periodontitis were treated with topical application of melatonin (1% orabase cream formula) for 20 days by. The rest of the patients with diabetes and periodontitis and healthy subjects were treated with a placebo of orabase cream. We measured the gingival index by exploring the percentage of standing teeth bleeding on probing. The periodontogram was performed with a Florida Probe. In the diabetic patients who were given topical melatonin, there was a statistically significant decrease in the two clinical parameters. By contrast, in diabetic patients who were given the topical placebo, there was no statistically significant variation. In patients with diabetes and periodontal disease, treatment with topical melatonin was associated with a significant improvement in the gingival index and in pocket depth, and a statistically significant reduction in concentrations of interleukin-1?, interleukin-6 and prostaglandin E2 in gingival crevicular fluid.