Background/Purpose: The mechanism responsible for the beneficial effects of extracorporeal photochemotherapy (ECP) remains unknown. In the rat model of experimental allergic encephalomyelitis (EAE), the transfer of encephalitogenic cells (EAE cells) induces transient passive EAE, followed by resistance to subsequent disease induction through immunization with central nervous system antigens (active EAE). Methods: We tested whether ECP exerts its therapeutic effect by inducing an immune response targeted on circulating pathogenic T-lymphocytes, which results from their increased immunogenicity. We compared the potential of untreated versus ECP-treated encephalitogenic cells to transfer passive EAE and protect against active induction of the disease. The UVA irradiation conditions were derived from intensive ECP protocols used in human clinical studies. Results: Animals receiving untreated cells showed clinical symptoms following cell transfer but not after subsequent immunisation, whereas those receiving ECP-treated cells remained healthy following cell transfer but experienced clinical symptoms after subsequent immunisation. However, these symptoms were less marked than in control naive rats. Conclusion: Under these ECP protocol conditions, ECP-treated cells have no greater active stimulatory potential for the recipient immune system than untreated cells, since they are less effective at triggering the response that causes the resistant state to active EAE. We suggest that intensive ECP protocol may have deleterious effects with a risk of relapses after treatment discontinuation. The search for the irradiation threshold that would inhibit the T-cell pathogenic properties, but retain their ability to educate the immune system, remains a major research challenge.