We have previously reported the molecular signature of murine pathogenic T_H17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ⁺IL-17⁺ (T_H1/17) and IFN-γ⁻IL-17⁺ (T_H17) CD4⁺ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to T_H17 cells, T_H1/17 cells have gene signatures with marked similarity to mouse pathogenic T_H17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that T_H1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in T_H17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory T_H17 cells, which can be used to both identify pathogenic T_H17 cells and to measure the effect of treatment on T_H17 cells in human autoimmune diseases.