Provided are a method, system, and article of manufacture for credit depletion notification for transmitting frames between a port pair. Credits indicate a number of outstanding frames a first device may transmit to a second device. The credits are decremented in response to transmitting a frame to the second device. The credits are incremented in response to receiving a ready code from the second device indicating that the second device processed the transmitted frame. A determination is made as to whether additional credits are needed for communicating frames from the first device to the second device. A credit depletion notification is sent to the second device in response to determining that the additional credits are needed for communication with the second device.