I have a new PCI serial card, being used on a Ubuntu 14.04 box.
It's serial ports show up as /dev/ttyS4 and /dev/ttyS5.
$ dmesg | grep ttyS
[ 0.732690] 00:03: ttyS0 at I/O 0x3f8 (irq = 4, base_baud = 115200) is a 16550A
[ 0.733604] 0000:06:04.0: ttyS4 at I/O 0xd010 (irq = 16, base_baud = 115200) is a XScale
[ 0.733700] 0000:06:04.0: ttyS5 at I/O 0xd000 (irq = 16, base_baud = 115200) is a XScale
$
I can set the baud rate of ttyS4 once after a reboot...
$ sudo /bin/stty -F /dev/ttyS4 115200
$
A second attempt yields an error...
$ sudo /bin/stty -F /dev/ttyS4 115200
/bin/stty: /dev/ttyS4: Input/output error
$
ttyS5 works fine...
$ sudo /bin/stty -F /dev/ttyS5 115200
$
and a second time...
$ sudo /bin/stty -F /dev/ttyS5 115200
$
The problem was that the card was doing some sort of auto-baud detection on ttyS4 (which had a cable plugged in), but not on ttyS5 (which didn't).
I've thrown the card away and am using a USB adapter now.