[6] The series initially follows Drew, a therapist and newly divorced father with B-positive blood who needs a kidney donor.

The sitcom is inspired by the true story of series creator Marco Pennette, who received a kidney transplant in 2013.

Meanwhile, Gina asks Drew to counsel a stubborn resident named Harry (Héctor Elizondo) who is having a hard time dealing with his wife's terminal illness.

Harry is tough on a meek Drew but eventually warms up to the guy and invites him to spend time playing billiards.

[57] On September 1, 2021, Lavin, Higgins, and Stephens were promoted to series regulars while Hector Elizondo, Jane Seymour, Ben Vereen, Celia Weston, Jim Beaver, and Anna Maria Horsford joined cast in recurring roles for the second season.

On October 5, 2021, it was reported that Michelle Ortiz joined the cast in a recasting, replacing Rosa Salazar for the second season.

The website's critics consensus states, "B Positive's familiar sitcom trappings are elevated by its charming cast—especially the weird and winsome comedic stylings of Tony winner Annaleigh Ashford.