Background: Vitiligo is an acquired idiopathic hypomelanotic disorder of a puzzling aetiology.Photochemotherapy (PUVA) and phototherapy are considered the conventional treatment for generalizedvitiligo. Up to 80% of lesions usually respond to phototherapy and photochemotherapy but there arecertain areas known to resist repigmentation even with some surgical modalities.Aim of the work: is to study the difference between areas responding to PUVA and thoseresistant to it as regards the immunological status before treatment and the response totreatment.Materials and Methods: A prespective controlled clinical study was done in which twenty patients withactive generalized vitiligo were included in the study. Lesional and perilesional biopsies were taken fromareas expected to respond to PUVA before and after starting repigmentation; lesional and perilesionalbiopsies were taken from responding and resistant lesions. We measured the MHC II and ICAM 1expression on the surface of langerhans cells (identified by CD1a) and melanocytes (identified by Melan A)being two important molecules in the interaction between melanocytes, langerhans cells and lymphocytes.Results: Before PUVA therapy resistant areas showed: significantly lower perilesional melanocytes,significantly lower langerhans cells density and significantly lower epidermal MHC II. After PUVA therapy,there was a rise in perilesional melanocyte count in both responding and resistant areas but this rise wasnot statistically significant. However perilesional melanocytes were still lower in resistant areas. There wassignificant decrease in the number of langerhans cells and MHC II in both responding and resistant lesions.ICAM-1 showed no significant difference between resistant and responding areas neither before nor aftertreatment.Conclusion: On comparing PUVA resistant lesions of acral vitiligo to responding lesions before treatmentthere was a significantly lower number of perilesional melanocytes, langerhans cells as well as epidermalMHC stained cells. These findings might indicate either higher cytotoxicity at these sites or a difference inthe immunological status. After PUVA therapy the response of resistant lesions was similar to respondinglesions as regards immunohistochemical level. The melanocytes showed mild increase in perilesional skin,langerhans cells and MHC II positive epidermal cells dropped significantly. Inspite of these changes,responding lesions repigmented but the resistant lesions failed to repigment. The PUVA induced changesthat stimulate repigmentation in responding lesions occur in resistant lesions but seems not to be enoughto achieve equal repigmentation.