PURPOSE: To examine the effects of a negatively charged nanostructured curcumin microemulsion in experimental ulcerative colitis (UC) in rats. METHODS: Four percent acetic acid was used to induce UC. The animals were treated for seven days and randomly assigned to four groups: normal control (NC), colitis/normal saline (COL/NS), colitis/curcumin (COL/CUR), and colitis/mesalazine (COL/MES). The nanostructured curcumin was formulated with a negative zeta potential (-16.70 +/- 1.66 mV). Dosage of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), interleukin 6 (IL-6), and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase), macro and microscopic evaluation of the colon tissue were analyzed. RESULTS: The COL/CUR group had a higher level of antioxidant enzymes compared to the COL/MESgroup. The levels of TNF-alpha, IL-1beta and IL-6 were significantly lower in the colonic tissue of the COL/CUR group rats, when compared to the COL/NS and COL/MES groups (p < 0.001). The presence of ulcers in the colonic mucosa in rats of the COL/NSgroup was significantly higher than in the COL/MES group (p < 0.001). In the NC and COL/CUR groups, there were no ulcers in the colonic mucosa. CONCLUSIONS: The nanostructured microemulsion of curcumin, used orally, positively influenced the results of the treatment of UC in rats. The data also suggests that nanostructured curcumin with negative zeta potential is a promising phytopharmaceutical oral delivery system for UC therapy. Further research needs to be done to better understand the mechanisms of the negatively charged nanostructured curcumin microemulsion in UC therapy.