First of all, I'm assuming you mean PCIe 2.1.
PCI 2.1 is an old specification for the legacy PCI bus that added 66MHz operation as an option.
It depends on which motherboard you have.
PCIe 2.1 graphics cards have been reported to have issues with some PCIe 1.0 motherboards. If your motherboard is PCIe 2.0, you'll have no problems.
Generally, the improvement gained by newer versions of PCIe is mostly meaningless for PC gaming. With PCIe 2.0, running a x16 card in a x8 slot only results in a 1-2% performance penalty in game performance. Most multi-card setups use x8 or even x4 slots for secondary or tertiary cards for this reason. Even scaling PCIe 2.0 back to x4 gives about 95% of x16 performance. Graphics cards simply don't need all the bandwidth that 16 PCIe 2.0 lanes provide.