This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively (P<0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity.