A flexible input/output (I/O) expansion card connection and communication technique are provided. The flexible I/O expansion card is, in some examples, a mezzanine expansion card that may be a single width mezzanine expansion card, a double width expansion card, or a quad width expansion card. Multiple connectors on a mainboard provide a slot to receive plug in (insertion) of an expansion card. A slot is associated with a communication bus (e.g., Peripheral Component Interconnect (PCI)) established between the expansion card and an associated processor. The expansion card (or more than one expansion card) may be inserted in multiple orientations with respect to the multiple connectors. Automatic adjustment of communication on the communication bus may be implemented via one or more hardware level and/or software assisted translations to allow the mezzanine expansion card to function in a normal or a reverse (180 degrees relative to normal) orientation.