It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD). In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale-17 items (Ham-D) score ≥18 were randomly assigned to either celecoxib (200mg twice daily) or placebo in addition to sertraline (200mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6. The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI)=0.42(0.30 to 0.55) pg/ml, t(35)=6.727, P<0.001) as well as Ham-D scores (mean difference (95%CI)=3.35(1.08 to 5.61), t(38)=2.99, P=0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P=0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r=0.378, P=0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r=0.673, P<0.001). We did not measure other inflammatory biomarkers. We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant (Registration number: IRCT138903124090N1).