Defects in T cell function in cancer patients might influence their capacity to mount efficient anti-tumor immune responses. Here we identified highly reduced IL-4-, IL-10- and IL-21-induced phosphorylation of STAT6 and STAT3 in tumor infiltrating T cells (TILs) in follicular lymphoma (FL) tumors, contrasting other non-Hodgkin lymphoma TILs. By combining phospho-protein specific flow cytometry with several T cell markers, we identified that CD4(+)CD45RO(+)CD62L(-) FL TILs were largely non-responsive to cytokines, in contrast to the corresponding autologous peripheral blood subset. We observed differential expression of the inhibitory receptor PD-1 in FL TILs and peripheral blood T cells. Furthermore, CD4(+)PD(-)1(hi) FL TILs, containing T(FH) and non-T(FH) cells, had lost their cytokine responsiveness, whereas PD-1(-) TILs had normal cytokine signaling. However, this phenomenon was not tumor-specific, since tonsil T cells were similar to FL TILs. FL tumor cells were negative for PD-1 ligands, but PD-L1(+) histiocytes were found within the T-cell rich zone of the neoplastic follicles. Disruption of the microenvironment and in vitro culture of FL TILs could restore cytokine signaling in the PD-1(hi) subset. Since FL TILs in vivo likely receive suppressive signals through PD-1, this provides a rationale for testing PD-1 Ab in combination with immunotherapy in FL patients.