The effect of chemotherapy or chemotherapy followed by total body irradiation and autologous bone marrow transplantation on clinical status and lymphocyte function was evaluated in 79 dogs with spontaneous lymphoma. Advanced disease led to the early deaths of 28 dogs (35%), and 24 dogs (30%) administered chemotherapy had a mean survival time of 85 days (range 33–199 days). Survival for eight dogs receiving chemotherapy and BCG was comparable to that produced by chemotherapy only. Thirteen dogs administered chemotherapy followed by irradiation and autologous marrow grafts had survival times ranging from 59 to > 807 days (median 222 days) with median unmaintained clinical remission lasting 151 days. Most treated dogs experienced improvement in health, reduction in lymph node sizes and normalization of liver function. Lymphocyte reactivity to mitogens and streptolysin-O antigen by untreated and treated lymphoma dogs was depressed (P<0.05) compared to response of normal lymphocytes. Mixed leukocyte reactivity of irradiated lymphoma dogs was impaired in the first 150 days post-irradiation and returned to normal values after 150 days. Lymphocyte responses of irradiated normal dogs paralleled those seen in lymphoma dogs. Mixed leukocyte reactivity was not correlated with tumor rejection since eight of nine dogs evaluated following irradiation relapsed during a period of vigorous reactivity to allogeneic stimulating cells.