Background: Curcumin as a polyphenolic compound has a potential capacity to reduce autoimmune reactions by skewing the balance of Thelper1 (Th1)/regulatory T cells (Treg) toward Treg cells. However, the low absorption and bioavailability of this agent have prompted researchers to use various drug delivery systems such as phytosomes to reduce these drawbacks. To date, few studies have evaluated the effects of phytosomal curcumin (nano-curcumin) on immune responses. Hence, we compared the modulatory effects of curcumin in free and phytosomal form on the expression of Th1 and Treg transcription factors, T-bet (T-box-containing protein) and Foxp3 (forkhead box p3), respectively, in a collagen-induced arthritis model (CIA). Materials and Methods: Following the induction of CIA, splenocytes were isolated and re-stimulated with collagen in the absence or presence of two different doses of curcumin in free and phytosomal form. Then, expression of T-bet and Foxp3 was assessed by real-time PCR. Results: The expression of T-bet was reduced in curcumin and phytosomal curcumin groups rather than in the untreated group. The level of T-bet was not significantly different between free and phytosomal groups. Moreover, mRNA expression of Foxp3 enhanced after treatment with curcumin, while phytosomal curcumin groups showed no difference in comparison with the untreated group. Conclusions: curcumin in nano/free form showed a modulatory effect on the expression of T-bet. However, only free-form enhanced Foxp3 expression, which could be owing to the low amount of curcumin in the phytosomal complex rather than free-form at the same dose or due to leakage of curcumin from the complex.