Follicular lymphoma is classified into grades (G)1, 2, and 3 based on the number of centroblasts in neoplastic follicles. However, the accuracy of manually counting these centroblasts is limited by certain cells (large centrocytes, follicular dendritic cells, and histiocytes) that could mimic centroblast morphology. The reproducibility of follicular lymphoma grading is dependent upon observer experience; therefore, significant variations occur. This study is to explore a more objective, reliable way of grading follicular lymphoma using a quantitative imaging system in conjunction with immunostains with antibodies to proliferation markers MIB-1 and S-phase kinase-associated protein 2 (SKP2). Fifty-eight follicular lymphomas (G1, n = 23; G2, n = 18; and G3, n = 17) were studied on formalin-fixed, paraffin-embedded sections. Positive nuclear staining of both Ki-67 and SKP2 was recorded using the quantitative Clarient ACIS II system (Aliso Viejo, CA, USA). Ten high-power fields (x400) from randomly selected neoplastic follicles were counted by a pathologist blinded to the previously assigned morphologic grade. The results show that the percentages of Ki-67+ and SKP2+ cells significantly differ among the different grades of follicular lymphoma. A higher grade of follicular lymphoma is associated with a higher percentage of Ki-67+ and SKP2+ cells. The overall SKP2+% cells are substantially lower than Ki-67+% cells in the same grade of follicular lymphoma. Statistical significance is observed in Ki-67+ cells between follicular lymphoma G1 and follicular lymphoma G3 and between G1 and G2. In contrast, statistical significance is noted in SKP2+% cells between follicular lymphoma G1 and follicular lymphoma G3 and between follicular lymphoma G2 and follicular lymphoma G3. The findings suggest that the SKP2 expression has better discrimination with grades of follicular lymphoma than Ki-67 expression. Compared with traditional methods, quantitation of SKP2 expression using a quantitative image analysis system might be a useful and objective approach in grading follicular lymphoma.