The increase of cytoplasmic Ca2+ concentration (Δ[Ca2+]c) in response to antigenic stimulation is a critical step of signals activating immune responses. In addition, the voltage-gated K+ channels (Kv) in T lymphocytes draw attention as an effective target of immune-modulation. Caffeic acid phenethyl ester (CAPE), an active component of propolis, shows strong anti-inflammatory effects and T cell suppression. Although various mechanisms have been suggested for the action of CAPE, the effects of CAPE on intracellular Ca2+ signaling and ion channels are unknown. Here we investigated the effects of CAPE on Δ[Ca2+]c, Ca2+-release activated Ca2+ current (ICRAC), and Kv current (IKv) in Jurkat T cells, and on Ca2+-activated K+ channel current (ISK4) overexpressed in HEK-293 cells. ICRAC was induced by dialyzing T cells and Orai1/STIM1 overexpressing HEK293 cells with InsP3/BAPTA-containing pipette solution. CAPE concentration-dependently decreased both T cell receptor (CD3)- and thapsigargin-induced Δ[Ca2+]c. The phosphorylation of PLCγ1 by CD3 stimulation was not affected by CAPE. ICRAC was almost completely blocked by 25 μM CAPE. CAPE also inhibited the IKv and ISK4. Albeit the strong inhibition of Ca2+ influx via CRAC, the suppression of IL-2 secretion by CAPE was similarly observed in human peripheral T cells when the CRAC pathway was circumvented by ionomycin. Although the unspecific inhibition of ion channels by CAPE suggested an intriguing mechanism, the effects of CAPE on signaling pathways other than ICRAC seem to play dominant roles in the immunomodulation by CAPE.