The primary objective was to assess the safety of a new toothpaste formulation containing cetylpyridinium chloride (CPC) and cymenol as active agents. In addition, clinical efficacy and patient perception were evaluated. A 6-week randomized clinical trial was designed and patients were randomly allocated to use a test or control dentifrice. Adverse effects were assessed at 3- and 6-week follow-up visits, together with the following clinical parameters: Turesky plaque index (PlI), bleeding on marginal probing (BOMP), bleeding on probing (BOP) and Gründemann modification of the stain index (GMSI). Patient-reported outcome measures (PROMs) were also evaluated. A total of 60 patients were randomized and 55 were finally included in the analysis (test, 29; control, 26). Both toothpastes were safe and well tolerated by the patients. Statistically significant differences between test and control groups were observed for BOP changes between baseline week 6 (p = 0.031) and lower levels of plaque were registered in the test group at the 3- and 6-week visits (p < 0.05). No differences were observed for staining or PROMs. The use of a toothpaste containing CPC and cymenol was safe and not associated with any adverse effects. Significantly better clinical results were observed for the test group in terms of PlI levels and BOP reductions.