OBJECTIVE Abundant evidence indicates the involvement of CD4(+), CD8(+), and CD4(+)CD25(+) T lymphocytes in the induction and/or protection of rheumatoid arthritis (RA). We aimed to investigate the modulatory effect of Nigella sativa (NS) oil on the selected T cell subset percentage in females with RA. METHODS A randomized, double-blinded placebo-controlled, 2 months, parallel-group clinical trial was conducted. Forty-three female patients (20-50 years) with mild to moderate RA were recruited and assigned into NS (n = 23) and placebo (n = 20) groups to receive one gram of NS oil, or starch, capsule in two divided doses, respectively. The disease activity scores of 28 joints (DAS28) were calculated and percentages of CD4(+), CD8(+), and CD4(+)CD25(+) T cells were examined using flow cytometry. RESULTS Treatment with NS led to significant reduction of the serum high-sensitivity C-reactive protein (hs-CRP) level and DAS-28 score and an improved number of swollen joints compared with baseline and placebo groups. A relatively comparable CD4(+) T cell percentage was observed in the NS and placebo groups either in baseline or the end of study. The treatment also resulted in reduced CD8(+), and increased CD4(+)CD25(+) T cell percentage and the CD4(+)/CD8(+) ratio as compared to placebo and baseline. A negative significant correlation between changes in CD8(+) and changes in CD4(+)CD25(+) T cells and a positive significant correlation between changes in CD4(+)CD25(+) T cells and changes in the CD4(+)/CD8(+) ratio was observed in the NS group. CONCLUSIONS This study gives strength to the potential relevance of NS in clinical management of RA through modulation of T lymphocytes.