Specific cytokines and the costimulatory protein CD40 play role in inducing immunoglobulin (Ig)A production by B cells in the humoral immune response. However, to date, the role of these mediators was not investigated in chronic periodontitis. Therefore, the aim of this study was to assess the local levels of interleukin (IL)-21, IL-21 receptor (IL-21R), IL-4, IL-10 and CD40 ligand (CD40L) on chronic periodontitis subjects and their relationship with the salivary levels of IgA. Gingival biopsies and un-stimulated saliva were collected from chronic periodontitis (n = 15) and periodontally healthy (n = 15) subjects. The mRNA levels of IL-4, IL-10, IL-21, IL-21R, CD40L in the gingival biopsies were evaluated by quantitative real-time polymerase chain reaction. The salivary levels of IgA and the levels of IL-4 and IL-10 in the gingival biopsies were analyzed by ELISA. The mean levels of IgA were significantly higher in the chronic periodontitis compared to periodontally healthy group (P < 0.05). The mRNA levels for IL-21 was higher (P < 0.05) in the chronic periodontitis when compared to the healthy group. However, the expression of IL-21R and CD40L did not differ between groups. The IL-10 was significantly elevated at mRNA and protein levels in chronic periodontitis when compared to periodontally healthy group (P < 0.05). Conversely, the mRNA levels as well as the protein amount of IL-4 were significantly lower (P < 0.05) in chronic periodontitis than healthy ones. In conclusion, the upregulation of IL-21 and IL-10 and downregulation of IL-4 in periodontitis tissues may be collectively involved in the increased levels of salivary IgA in chronic periodontitis subjects.