We examined the cross-reaction between photosensitivity to piroxicam (PXM) and contact sensitivity to thiosalicylate (TOS) by a lymphocyte proliferation test (LPT) in guinea pigs. The lymph node cells (LNCs) plus peritoneal exudate cells (PECs) from guinea pigs contact-sensitized with TOS remarkably cross-proliferated to PXM under UVA (4 J/cm2) irradiation. On the other hand, the PXM-photosensitized LNCs+PECs also cross-proliferated to TOS. From these results, the reciprocal cross-reaction between TOS-hypersensitivity and PXM-photosensitivity was reconfirmed by the in vitro LPT, indirectly indicating that the PXM-photosensitivity is a cell (probably T cell)-mediated PXM photoallergy in its nature. The TOS-primed LNCs+PECs did not cross-proliferate to UVA (4 J, 180 J or 500 J/cm2)-pretreated PXM (UVA-PXM) although it is supposed to contain several photoproducts of PXM. Furthermore, the TOS-primed LNCs developed a remarkable proliferative cross-response to the PECs pulsed with PXM under UVA (4 J/cm2) irradiation (photo-PXM-modified PECs), but not to the PECs pulsed with PXM or UVA-PXM. Therefore, it is presumed that the cross-reactive molecule, which is easily formed from PXM under UVA irradiation, is unstable, and that the formation of complete antigen by the generation of this molecule and its photobinding needs the coexistence of PECs, PXM and UVA irradiation at the same time in the culture.