Hand mirror cell (HMC) lymphoid leukemia is an unusual variant of acute lymphocytic leukemia (ALL) in which the bone marrow lymphoblasts manifest distinctive hand mirror morphologic features. Reported here is a 66-year-old woman with HMC lymphoid leukemia whose clinical course was characterized by 12 months of initial disease stability while she was receiving no chemotherapy; a prompt response to cyclophosphamide, vincristine, and prednisone therapy once instituted; and a hyperleukocytic episode (leukocyte count 607,000/mm3), which resulted in her death after 22 months of disease. This patient and 13 other reported adults (15 years and older) with HMC lymphoid leukemia (greater than 40% bone marrow HMC) are reviewed. HMC lymphoid leukemia appears to differ from typical adult ALL in that it has a female predominance, a relatively indolent early clinical course that lasts 1 year or longer, and it manifests the possibility of survival for 1 or 2 years despite the failure to achieve a complete remission with chemotherapy. Phenotypically, the HMC leukemic cells from all adults evaluated were null cells, Ia-positive, TdT-positive, and stained positively with acid phosphates, which suggests that HMC lymphoid leukemia is a variant of non-T, non-B-ALL. HMC lymphoid leukemia in adults appears to be a distinctive clinicopathologic entity.