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Rejection was a condition where the connection between a Trill host and symbiont is lost. Rejection was measured by a drop in isoboramine levels, with levels below 40% of normal being harmful or fatal to the host and symbiont. During rejection, the symbiont had to be removed from the host to prevent it from dying, sacrificing the host in the process.

In 2371, Jadzia Dax experienced a series of suppressed memories (initially believed to be hallucinations), which caused her isoboramine levels to decline rapidly. Although the Symbiosis Commission attempted to stabilize the connection, Jadzia's condition deteriorated as her body began to reject the Dax symbiont. Jadzia was saved from rejection when the suppressed memories were brought to the surface and reintegrated with the rest of Dax's memories. (DS9: "Equilibrium")

Rejection could occur when a symbiont was implanted into a non-Trill host. In 2367, the host of the symbiont Odan was injured from an attack on the shuttlecraft he was traveling on; the injuries were severe, and required the removal of Odan. He could not survive outside a host for more than a few hours and a suitable Trill host was at least 40 hours away, so William T. Riker voluteered to serve as a temporary host. However, Riker's body began to reject Odan, and Odan insisted that he be removed before he caused permanent damage to Riker. Ultimately, Odan was placed in a new host, and Riker was unharmed. (TNG: "The Host")

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