Objectives The aim of this study is to explore the association of podocyte injury with clinical features and outcomes in mesangial proliferative (Class II) lupus nephritis (LN). Methods We conducted a retrospective and clinicopathologic analysis with 576 LN patients with renal biopsy and screened 58 patients with Class II LN. Then, the 58 cases were divided into 4 groups based on the degree of podocyte damage and immune complex (IC) deposits on light microscope (histological and immunofluorescence) and electron microscope: Podocyte Injury Group, IC deposits Group, Podocyte Injury and IC Group, and Less-lesion Group. Clinical and pathologic information was collected from the patients’ medical records at the time of the kidney biopsy and at follow-up. The data of demography, clinical parameters, therapy, remission, and relapse rates were analyzed and compared across groups. Results A significant difference was observed in the ages of patients among four Class II LN groups. The onset age of patients with FPE ≥ 50% was significant later. The frequency of thrombocytopenia was statistically different among the four groups and the patients with FPE ≥ 50% had lower frequency of thrombocytopenia. Patients with FPE ≥ 50% had lower serum albumin, eGFR, and elevated proteinuria and serum lipids. In this study, most patients received glucocorticoids in combination with immunosuppressants. Among the 4 groups, the use of ACEI/ARBs was highest in the podocyte injury group. There was a statistical difference in the renal relapse rates among the 4 Class II LN groups. Moreover, the recurrence rate was higher in the FPE ≥ 50% group. Conclusion Our data identified Class II LN patients with podocyte injury (FPE ≥ 50%) present prominent renal damage and higher rate of renal relapse, suggesting more aggressive treatment and close follow-up for these patients.