The immunological reactivity of 40 untreated patients with Hodgkin’s disease was studied by some in vitro tests exploring the lymphocyte function, The response of lymphocytes to PHA was markedly depressed in the advanced stages of the disease, but it appeared significantly decreased also in the initial stages when a suboptimal concentration of the stimulant was used to activate the cells in culture. No significant correlation was found between the depressed lymphocyte response to PHA and a particular histologic pattern of the disease, even though patients with lymphocyte predominance and nodular sclerosis usually showed the best responses. The decrease of PHA-stimulability was not dependent on the activity of free serum factors or by the usually high number of phagocytic cells contaminating the standard quantity of lymphocytes in culture. Nor was it due, at least in the initial phases of the disease, to a depletion of circulating cells able to respond to PHA. In fact, the percentage of Ig-bearing lymphocytes in the peripheral blood was usually normal; E rosette-forming cells were present in normal number in the initial stages of the disease and their percentage was markedly decreased only in a very small number of patients with advanced disease. Virtually all the patients with positive delayed-type skin reactions to PPD and Candida, but also many of those without skin reactivity showed a significant in vitro response to the same antigens. The responding capacity in MLC of lymphocytes was not significantly reduced in comparison to that of normal controls; the stimulatory efficacy of the same cells was decreased in some patients but, at group level, did not appear significantly lower of that of normal controls. An increased level of IgE immunoglobulin could be demonstrated in the serum of many patients with HD. The data here reported demonstrate that a functional defect of lymphocytes is a very frequent finding in untreated patients with HD; they also show that of the tests available for the study of lymphocyte function, the PHA-stimulability seems to be the more sensitive and its alteration always precedes the development of T lymphopenia.