Background: Periodontal disease is the most common multifactorial disease, afflicting a very large proportion of the adult population. Periodontal disease secondarily causes increases in the serum levels of C-reactive protein (CRP) and other markers of inflammation. An increased level of CRP reflects an increased risk for cardiovascular disease. The aim of the current randomized clinical trial was to evaluate the short-term effect of a combination of dipyridamole and prednisolone (CRx-102) on the levels of high-sensitivity (hs)-CRP, proinflammatory markers in blood, and clinical signs of periodontal disease. Methods: Fifty-seven patients with >= 10 pockets with probing depths >= 5 mm were randomized into two groups in this masked single-center placebo-controlled study: CRx-102 (n = 28) and placebo (n = 29). hs-CRP levels, inflammatory markers (interleukin [IL]-6, -1 beta, -8, and -12, tumor necrosis factor-alpha, and interferon-gamma [IFN-gamma]), bleeding on probing (BOP), and changes in probing depths were evaluated. The subjects received mechanical non-surgical therapy after 42 days, and the study was completed after 49 days. Results: At day 42, the differences in the hs-CRP, IFN-gamma, and IL-6 levels between the two groups were statistically significant (P<0.05), whereas no difference was found for the other inflammatory markers. There was no change in probing depth or BOP between the two groups. Conclusion: The administration of CRx-102 resulted in significant decreases in hs-CRP, IFN-gamma, and IL-6, but it did not significantly change BOP or probing depths.