Background: Diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) is an aggressive neoplasm with a dramatic increase in its incidence over the last several decades. The t (14;18) is the most common reported translocation in this lymphoma resulting in high levels of bcl-2 protein. This study was undertaken to investigate the frequency of t (14;18) and bcl-2 overexpression in DLBCL and their effect on clinical outcome of patients to help in diagnosis and treatment.Material and Methods: Fifty cases of diffuse large B-cell non- Hodgkin’s lymphoma were subjected to clinicopathologic evaluation, immunohistochemical staining for bcl-2 (Mouse IgG1/K, clone100/D5) and Molecular studies in the from of DNA extraction and PCR amplification for detection of bcl-2/JH rearrangement using nested oligonucleotides for both mbr and mcr breakpoint regions. Cases were followed-up for 3 years.Results: The frequency of bcl-2 protein overexpression was 58%. It was significantly higher in stage III & IV(p=0.006), in high IPI compared to low IPI (p=0.003) and with lack of response to therapy (p=0.003). The frequency of bcl-2 rearrangement [t (14;18)] was 16% of which 2% within the mbr and 14% with mcr rearrangement. It was significantly higher in stage III &IV (p=0.016) with high score IPI (p=0.046) and lack of response to therapy (p=0.045). No significant association was found between bcl-2 protein overexpression and bcl-2 gene rearrangement. The 3-years progression free survival was statistically significant with stage, IPI and response to therapy. It was encountered more in the negative cases for bcl-2 protein overexpression and in the negative cases for bcl-2 rearrangement.Conclusion: The frequency of bcl-2 rearrangement [t (14;18)] in Egyptian DLBCL is 16% which is within the range world wide but with preferential breakage of bcl-2 gene outside mbr. It has a significant impact on clinical outcome while bcl-2 protein overexpression should be considered a new independent biologic prognostic parameter in DLBCL with a recommendation to be incorporated into the design of treatment strategies.