Burkitt lymphoma (BL) and Burkitt-like lymphomas (BLL) are clinically and biologically aggressive B-cell malignancies. Brief-duration, high intensity multidrug regimens with central nervous system (CNS) prophylaxis have proven to be effective, with published series of adult patients documenting complete response (CR) rates of 80 to 100 percent and 2-year event-free survival (EFS) rates ranging from 60 to 90 percent. Based upon the known sensitivity of BL to cyclophosphamide and favorable results reported from the Dana Farber Cancer Center using high-dose CHOP in diffuse aggressive lymphomas, we tested a regimen designed to maximize the administered dose of cyclophosphamide while eliminating other agents commonly used in BL protocols. Eleven patients with Burkitt or Burkitt-like lymphoma were treated with 4 cycles of a 5-drug regimen, called high-dose CHOP, which contains a cyclophosphamide dose of 4 gm/m2 with each cycle. Intrathecal methotrexate and midcycle high-dose methotrexate were added as CNS prophylaxis. Ten patients achieved a complete response (91 percent) and with a median follow up of 38 months, the 3-year EFS is 64 percent and the 3-year overall survival (OS) is 72 percent. Three patients recurred after the achievement of a CR. Treatment-related toxicities included myelosuppression, neutropenic fevers/infections, and tumor lysis syndrome requiring hemodialysis in 2 patients. There were no treatment-related deaths and none of the patients had to discontinue therapy secondary to toxicity. In conclusion, the high-dose CHOP with midcycle methotrexate regimen produces response rates and EFS rates comparable to other regimens, with an acceptable toxicity profile. Utilization of high dose cyclophosphamide may eliminate the need for several other agents in Burkitt lymphoma regimens.