To evaluate the efficacy of metronidazole on cyclosporine-induced gingival overgrowth (GO), a prospective intra-subject double-blind longitudinal study was performed on six heart transplant patients with GO. All patients underwent scaling and root planing before any treatment. Metronidazole gel (Elyzol, Cabon) was then applied in two of the four anterior hemi-sextants of each subject, following a balanced random pre-programmed list, with a placebo gel being applied to the remaining two hemi-sextants. Plaque index (PI), bleeding on probing (BP) and probing depth (PD) were recorded for all teeth of the four anterior hemi-sextants before and at 1, 2, 3, and 4 months after gel application. A general linear model was fitted and ANOVA for repeated measurements with split-plot design and Chi-square analysis were used for statistical analysis. PD significantly decreased after 1 month following both treatments. Analogous results were obtained as regards PI and BP. No statistically significant difference was detected between results obtained with metronidazole and placebo. However, PD in the group of teeth treated with placebo significantly increased after 4 months, while PD values obtained from teeth treated with metronidazole remained statistically unchanged with respect to the 1st month. In conclusion, short-term results suggest that metronidazole and placebo are equally effective in reducing periodontal parameters and GO when associated with scaling and root planing. Long-term results, however, showed greater efficacy of metronidazole with respect to placebo in controlling cyclosporine-induced GO.