CAMPATH-1H is a humanized antilymphocyte monoclonal antibody (mAb) directed against the CD52 antigen expressed on normal and malignant lymphocytes. We report the results of a multicenter phase II trial using intravenous CAMPATH-1H in previously treated patients with nonbulky non-Hodgkin's lymphoma (NHL) or minimal residual NHL. Sixteen previously treated patients with nonbulky NHL and two patients with minimal residual NHL, were treated with CAMPATH-1H. Changes in peripheral blood lymphocyte subsets were analyzed by multiparameter flow cytometric techniques in eleven patients. The 18 patients enrolled in the studies received CAMPATH-1H for a median duration of 6 weeks (range, 3 to 14 weeks), and a median cumulative dose of 470 mg (range, 180 to 1185 mg). Two of the sixteen patients with nonbulky NHL achieved a complete response (CR) and one patient achieved a partial response (PR). One of the two patients with minimal residual NHL achieved a molecular CR. Infusional complications were seen with the majority of patients but were more common with initial infusions. Significant hematologic toxicity was also observed with grade (3/4) thrombocytopenia (n=10), grade (3/4) neutropenia (n=4) and grade 3 anemia (n=3). Due to excessive infectious complications observed with the patients enrolled, the trials were terminated early. Anti-tumor activity was demonstrated in a small subset of previously treated low-grade lymphoma patients with nonbulky or minimal residual disease. Future studies evaluating the effect of different drug schedules, modes of mAb administration, and concurrent use of prophylactic antibiotics/antiviral/antifungal agents to optimize anti-tumor activity and limit infectious toxicities are planned.