A total of 22 patients with advanced measurable colorectal carcinoma were treated with human lymphoblastoid interferon, 15 X 10(6) U/m2 im 3 times a week, in a trial designed to evaluate therapeutic activity, toxic effects, and biological response modification. One partial response (4.5% response rate) was observed which lasted 4 months. Sixty-eight percent of the patients required dose reduction for excessive toxicity, primarily constitutional symptoms. One patient developed phenobarbital toxicity, a previously undescribed side effect thought to be related to interferon-induced depression of hepatic microsomal enzymes required for drug metabolism. Treatment was associated with an increase in peripheral blood natural killer (NK) cell activity and the activity of an interferon-induced enzyme, 2'-5' oligoadenylate synthetase. The increase in NK cell activity was observed only in patients whose pretreatment NK cell activity was below normal. No induction of serum factors inducing differentiation of myeloid leukemic cell lines was documented. We conclude that human lymphoblastoid interferon, at the dose and schedule tested, has minimal antitumor activity as a single agent in advanced colorectal cancer and induces unacceptable toxicity in the majority of such patients. Recent literature suggesting a possible role for interferon alpha in combination with other drugs in the treatment of colorectal cancer is discussed.