Blissey and Jessie putting together the good luck charm
Sometime prior to Ignorance is Blissey, Jessie met a Blissey from Happy Town as a Chansey. She explains to James and Meowth that she had studied with the particular Chansey in a Pokémon Nurse School together, where they had become best friends. Jessie, unfortunately, did not qualify to become a nurse and quit the school, due to the fact that she is not a Pokémon, so she cannot learn the move Sing. Chansey had given part of the medal she had received as a nurse to Jessie so that they could remember each other.
Blissey made her first official appearance in Ignorance is Blissey. Ash and his friends had met up with Blissey in the Pokémon Center. Seeing that they were hungry, she prepared food for them but due to her over-enthusiasm, she spilled the food on them. A well-meaning yet clumsy Pokémon, the more Blissey tried to help, the more problems she caused. When Team Rocket tried to steal food from the center, Jessie met Blissey and they immediately recognized each other. Blissey then gave Team Rocket most of the food in the pantry. The others in the Pokémon Center soon found out and everyone blamed Blissey. Wanting to help her friend, Jessie pretended that she had tricked Blissey into giving them the food. She also faked attacking her to make Nurse Joy and the others believe her. They were soon thrown out, but not before Jessie whispered to her friend Blissey to keep it a secret.
Another Blissey reappeared in Uncrushing Defeat!, where she was seen with Nurse Joy in the Pokémon Center near Lake Acuity. She, along with Nurse Joy and Chansey, healed Ash's Pokémon after Ash lost to Paul in their Full Battle. Blissey was later seen watching a show Dawn put on with her Pokémon. She then watched as Ash took on Team Rocket and his Pokémon combined their attacks to blast Team Rocket off.
The Blissey from Happy Town was shown to be very clumsy, as seen when she fell after trying to give food to Ash and his friends. Despite that, the Happy Town Blissey had a good friendship with Jessie as they studied together in a Pokémon Nurse School when Blissey was a Chansey. Despite the fact that Chansey graduated from the school whereas Jessie didn't, their friendship stayed as Chansey gave Jessie half of the egg-shaped pendent to remember each other by. By the time Jessie got to reunite with Chansey who was now a Blissey, they were both happy to see each other and Jessie did everything she can to keep Blissey out of trouble.
Similar to the other recurring Pokémon that Nurse Joy have, both the Blissey from Happy Town and the other Blissey were shown to be very helpful.