Objective: The aim of this study was to compare the influence of topical metronidazole gel application and scaling and root planing on gingival crevicular fluid variables. Method and Materials: In a split-mouth study, 39 volunteers with chronic periodontitis were treated by metronidazole gel or scaling and root planing. Clinical attachment level and probing depth were recorded, and aspartate aminotransferase (AST) and total/transformed Alpha2-macroglobulin were determined in the gingival crevicular fluid at baseline, as well as after 3 and 6 months. Results: Both treatment procedures resulted in a gain of clinical attachment-0.67 mm for metronidazole and 0.50 mm for scaling and root planing (P .001)-at the end of the study. The median probing depth was significantly reduced by 0.66 mm for metronidazole and 1.00 mm for scaling and root planing (P .001) after 6 months. No change of AST was found. Alpha2-macroglobulin was significantly reduced for scaling and root planing and metronidazole after 3 and 6 months (P .001). No significant difference was found between the 2 procedures at any variable. Conclusions: These data suggest that Alpha2-macroglobulin reflects clinical changes better than AST and that metronidazole and scaling and root planing have the same influence on clinical outcome and biochemical variables in the gingival crevicular fluid. Keywords: alpha2-macroglobulin, aspartate aminotransferase, metronidazole gel, periodontal disease