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With Loretta sick and awaiting the results of a biopsy, Larry attempts to break it off with her before the results come back. Meanwhile, Jeff has an unusual encounter with Marty Funkhouser’s mentally unstable sister, Bam Bam (Catherine O’Hara).

Larry enlists the help of a doctor who’s renowned for encouraging cancer patients to remove themselves from bad relationships, to end things with Loretta. Meanwhile, he’s repulsed by Richard Lewis’ new girlfriend after he finds out she gave Richard a blowjob in the car.

After years of resistance, Larry agrees to do a Seinfeld reunion special when he realizes that giving Cheryl a major role might get her to take him back; Larry has another run-in with Susie after he supposedly saves her life by identifying that she has Lyme disease.

Larry burns his hand on an airplane hot towel, which affects his bra-unhooking technique and leads to his doctor reluctantly giving Larry his home phone number, which Larry proceeds to accidentally abuse. Meanwhile, he’s less than impressed when his expensive anniversary gift to Ted Danson and Mary Steenburgen is shunned in favor of Jeff and Susie’s daughter Sammy’s gift "from the heart", especially when they invite Jeff and Susie--but not him--to the restaurant from which he got the gift. Christian Slater guest stars.

Larry begins dating a disabled woman, Denise, who requires a wheelchair. They plan to attend a Kim Chee Yun recital being held by Larry’s friends, but Larry can’t contact his new date after Susie throws his BlackBerry into the ocean.

Larry and Jerry have problems with their assistant (Jillian Bell), who always wears clothes that expose her large stomach. Larry continuously offends Richard Lewis and inadvertently causes a "miracle" to occur.

Larry repeatedly runs into trouble at his golf club when he is blamed for two deaths, protests an unorthodox tipping policy, and forgets to turn off his BlackBerry. He also seeks to correct a spelling mistake on his mother’s gravestone, and makes a generous gift to his cousin Andy with unfortunate results.

Larry is forced to embrace his feminine side to cover for Jeff. Cheryl competes for a Seinfeld role. Larry loses his pants at Banana Republic. A law officer has an unusual name. John Schneider and Elisabeth Shue guest star as a couple who make Cheryl an indecent proposal. A bearded Ben Affleck has an uncredited cameo role exiting Banana Republic.

At the Seinfeld reunion table read, Larry befriends a 9-year-old who later constantly text-messages him. To calm Michael Richards’ nerves, Leon poses as a man who had battled Groat’s Disease. Jerry Seinfeld and Marty Funkhouser bond over a joke. Larry regrets lending his pen to Jason Alexander. Many Seinfeld supporting actors are shown rehearsing their roles in the reunion special, including Steve Hytner (Kenny Bania), Estelle Harris (Estelle Costanza), and Wayne Knight (Newman).

Larry is hopeful that his plan is working when Cheryl invites him over to review the Seinfeld reunion script. But when an attempt to right a wronged Mocha Joe causes Larry to miss the date, Cheryl turns to Jason Alexander for coaching.