Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for inflammation control and pain relief. However, while the adjunct use of NSAIDs is avoided for periodontal therapy because of related side effects, cyclic administration of NSAIDs may reduce or eliminate these effects. We evaluated the effect of a cyclic diclofenac potassium (DP) regimen on clinical parameters and levels of prostaglandin E2 (PGE2) and interleukin-1β (IL-1β) in the gingival crevicular fluid (GCF) of individuals with periodontitis. Materials and Methods: The study protocol was approved by the Ethics Committee (2000/071). Forty-one individuals with chronic periodontitis (33 men, 8 women) were divided into two groups (test and control) after initial periodontal therapy. During this 6-month, randomized, double-blind, placebo-controlled study, test (n = 28) and control (n = 13) groups were administered a cyclic regimen of DP (50 mg, twice daily) or placebo. Clinical measurements and GCF sample collections were made at baseline, 2, 4, and 6 months. GCF levels of PGE2and IL-1β were determined using enzyme immunoassay and enzyme-linked immunoassay kits, respectively. Results: At baseline, no significant differences existed between groups for plaque indices, gingival indices, bleeding on probing, probing depth (PD), or attachment levels (P > 0.05). Compared with the control group, cyclic regimen in the test group suppressed increased levels of PGE2found in GCF at the end of the study (P < 0.05). Significant differences for PD and relative attachment gain were also noted in favor of the test group (P < 0.05). Conclusions: These results suggest that a cyclic regimen of DP may be efficacious in the management of chronic periodontitis in adults.