The purpose of this study was to conduct a direct comparison of two dose regimens of minocycline to determine 1) whether they achieved crevicular fluid concentrations in a therapeutic range; and 2) the frequency of side effects. In a double-blind design, 30 patients divided into 2 groups were given either 100 mg minocycline or 200 mg minocycline per day for an 8-day period. The concentration of minocycline in the gingival clevicular fluid (GCF) at 8 days was 4.77 micrograms/ml for the 100 mg a day group and 5.97 micrograms/ml for the 200 mg a day group and at 15 days was 4.30 micrograms/ml for the 100 mg a day group and 4.17 micrograms/ml for the 200 mg a day group. There was no significant difference in the antibiotic concentration in the gingival crevicular fluid between the 2 groups. Reported adverse experiences to the minocycline were greater in the 200 mg a day group. Short-term changes in periodontal health as measured by plaque index, gingival index, pocket depth, and bleeding upon probing showed improvements in all parameters over the 15 day period. There were no significant differences in these parameters between the 100 mg a day and 200 mg a day group. At 8 days reduced levels of Porphyromonas gingivalis and Prevotella intermedia were achieved but they were not eliminated from infected subgingival sites in either group. Achieving bacteriostatic concentrations of GCF, fewer side effects, and the potential for better compliance suggests that a single daily dose of 100 mg minocycline should now be investigated for its efficacy in managing periodontal infections manifesting as periodontitis.