Previously, we identified protein spots with differential intensity between normal and tumor tissues of renal cell carcinoma (RCC) using 2D-DIGE. Here, we further examined two proteins, raf-1 kinase inhibitory protein (RKIP) and manganese superoxide dismutase (MnSOD), identified in one protein spot. Western blotting demonstrated that RKIP and MnSOD exhibited opposite expression patterns in normal and tumor tissues. Immunohistochemisry showed that MnSOD level significantly correlated with shorter progression-free survival. Gene-silencing assay demonstrated that RKIP and MnSOD had suppressive and promotive effects on tumor cell proliferation and invasion, respectively. Our findings reveal biological and clinical significance of RKIP and MnSOD in RCC.