T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases(1-3). The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gamma t (ROR alpha and ROR gamma t, respectively) have indispensible roles in the development of this cell type(4-7). Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both ROR alpha and ROR gamma t and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of ROR alpha and ROR gamma t, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors ROR alpha and ROR gamma t to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.