CD39 (ENTPD1) is expressed by subsets of pathogenic human CD4+ T cells, such as Th17 cells. These Th17 cells are considered important in intestinal inflammation, such as seen in Crohn’s disease (CD). Recently, CD161 (NKR-P1A) was shown to be a phenotypic marker of human Th17 cells. In this study, we report that coexpression of CD161 and CD39 not only identifies these cells but also promotes Th17 generation. We note that human CD4+ CD39+ CD161+ T cells can be induced under stimulatory conditions that promote Th17 in vitro. Furthermore, CD4+ CD39+ CD161+ cells purified from blood and intestinal tissues, from both healthy controls and patients with CD, are of the Th17 phenotype and exhibit proinflammatory functions. CD39 is coexpressed with CD161, and this association augments acid sphingomyelinase (ASM) activity upon stimulation of CD4+ T cells. These pathways regulate mammalian target of rapamycin and STAT3 signaling to drive the Th17 phenotype. Inhibition of ASM activity by pharmacological blockers or knockdown of ASM abrogates STAT3 signaling, thereby limiting IL-17 production in CD4+ T cells obtained from both controls and patients with active CD. Increased levels of CD39+ CD161+ CD4+ T cells in blood or lamina propria are noted in patients with CD, and levels directly correlate with clinical disease activity. Hence, coexpression of CD39 and CD161 by CD4+ T cells might serve as a biomarker to monitor Th17 responsiveness. Collectively, CD39 and CD161 modulate human Th17 responses in CD through alterations in purinergic nucleotide–mediated responses and ASM catalytic bioactivity, respectively.