Crews responded to the scene, in the area of East G Street & East McKinley Way, at about 8:30 a.m. after receiving a report of flames coming from the roof of a home, said Joe Meinecke of the Tacoma Fire Department.
As firefighters arrived on scene, the flames jumped to a second home next door and crews began spraying water on the burning structures.
Two people in the first home were taken to the hospital. One was listed in critical condition. The condition of the other person was not immediately available.
A couple and their 3-month-old baby were able to escape uninjured from the second home, said neighbor Lynnette Scheidt.
Fire officials later said the blaze was caused by someone in the first home who was smoking a cigarette near an oxygen tank.
Scheidt said she heard four explosions as the blaze grew in size, which may have been oxygen bottles igniting.
Meinecke said the first home is a total loss and the second home sustained heavy damage. The RV also was totally destroyed.
"It's pretty devastating," Scheidt said.
Two dogs are missing after the fire, but a third was found unhurt.