Residual tumor masses are sometimes found in non Hodgkin's lymphoma (NHL) patients after chemo-radiotherapy treatment. Radiologic findings do not differentiate lymphoma from fibrosis necrotic tissue. Surgical and histology reevaluation is the most reliable method of evaluation the viability of tumor residual masses. Sixty-three consecutive high-grade NHL were treated with F-MACHOP regimen. After 3 courses of F-MACHOP the response was evaluated clinically: twenty two (36%) achieved a clinical complete remission, 32 a clinical partial remission, 7 were non responders and two were not evaluable. An early pathological response evaluation was performed in 23 clinical partial responders. Fifteen (65%) patients had no evidence of NHL after pathological restaging and were considered as pathologic complete response and completed treatment with 3 additional courses F-MACHOP. Eight (35%), histologically positive, were defined as pathologic partial response and were crossed to salvage regimens. The 1 year actuarial event-free survival differed significantly according to clinical response after 3 courses of F-MACHOP and the outcome of clinical partial responders was highly dependent on the result of pathological restaging (87% for negative and 23% for positive). Our experience suggests that a significant proportion of clinical partial responses are histologically confirmed at pathological restaging when this procedure is performed early during treatment.