The　causal　relationship　between　conformational　folding　and　disulfide　bonding　in　protein　oxidative　folding　remains　incompletely　defined.　Here　we　show　a　stage-dependent　interplay　between　the　two　events　in　oxidative　folding　of　C-reactive　protein　(CRP)　in　live　cells.　CRP　is　composed　of　five　identical　subunits,　which　first　fold　spontaneously　to　a　near-native　core　with　a　correctly　positioned　C-terminal　helix.　This　process　drives　the　formation　of　the　intra-subunit　disulfide　bond　between　Cys36　and　Cys97.　The　second　stage　of　subunit　folding,　however,　is　a　non-spontaneous　process　with　extensive　restructuring　driven　instead　by　the　intra-subunit　disulfide　bond　and　guided　by　calcium　binding-mediated　anchoring.　With　the　folded　subunits,　pentamer　assembly　ensues.　Our　results　argue　that　folding　spontaneity　is　the　major　determinant　that　dictates　which　event　acts　as　the　driver.　The　stepwise　folding　pathway　of　CRP　further　suggests　that　one　major　route　might　be　selected　out　of　the　many　in　theory　for　efficient　folding　in　the　cellular　environment.