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After her regeneration, Romana continued to travel with the Fourth Doctor until she decided to stay in E-Space. She later returned to the main universe and rose to the office of Lady President of the High Council of Gallifrey.
The Fourth Doctor protested she had no right to assume the likeness of another person, so she went briefly through other forms (though retaining Astra's voice), only to settle back on Astra's. She also initially chose a style of dress that mimicked the Doctor's. The Doctor soon grew accustomed to her new form. He found this new incarnation easier to get along with than the last, at one point implying he considered her his best friend.
Romana met the Daleks and their creator, Davros, on their homeworld Skaro. There, she helped prevent both the Daleks and Movellans from gaining an advantage in their war.
She next went to Paris in 1979 where she and the Doctor stopped Scaroth from preventing the evolution of humanity. On Chloris, she was captured by a party of bandits.
When two spaceships, the Empress and the Hecate, collided, she helped separate them. She also helped to uncover a drug smuggling plot involving the lethal drug vraxoin, via Tryst's Continuous Event Transmuter and the Mandrels it contained.
Romana also helped prevent the Nimon from continuing their circle of taking over planets by posing as gods.
The Doctor and Romana went to Cambridge in 1979, intending to meet Professor Chronotis. The Doctor and Romana couldn't bring K9 to see him as they went punting. At that point, while they were on a punt up the Cam, the Doctor's first four incarnations, along with their companions, were taken by a time scoop to the Death Zone on Gallifrey. The Doctor and Romana were caught in a time eddy and failed to arrive in the Death Zone. They were released several hours later once Borusa was sealed in the Tomb of Rassilon. The Doctor, having gone "nowhere" for several hours, went back to the TARDIS, demanding everyone to put their bathing suits on as they were going to Brighton. The Doctor and Romana, though retaining memories of the punting trip, had forgotten they intended to visit Chronotis. The Doctor said that they had intended to be back "before lights out", but "went on somewhere else", according to Romana, after only being away from the TARDIS for two hours and twenty-one minutes.
The Doctor arrived in Brighton, but in the wrong season. K9 was damaged badly when he retrieved a ball she was playing with from the water. Romana visited the Leisure Hive, where she was present at the aborted rebirth of Argolin civilisation. Despite her protests, the Doctor removed the randomiser from the TARDIS, making them vulnerable to the Black Guardian finding them again.
On Tigella, Romana freed herself from the Bell Plants' harassment before she was captured by Gaztaks. She bluffed the Gaztaks by claiming she was leading them to the TARDIS before taking them around in circles. She lost them by leading them into the Bell Plants.
After forgetting all about the matter, the Doctor received an order from the Time Lords to return Romana to Gallifrey now they had found the segments to the Key to Time. Romana, having tasted a life of adventure with the Doctor and bonded with him, didn't want to return and sulked in her room. The Doctor's TARDIS entered a Charged Vacuum Emboitment, left the universe (N-Space) and entered another, smaller universe, E-Space.
They landed on the planet Alzarius. Romana was infected by an Alzarian spider. Its venom controlled her, making her complete tasks to help the Marshmen. The Doctor restrained her and she soon recovered.
Romana and the Doctor began searching for a CVE to return home. They came across a planet and landed upon it. They found an Alzarian, Adric, had stowed away on board. Romana was taken by a group of vampires as a sacrifice to the King Vampire. The Doctor rescued her and they resumed searching.
They arrived at the Gateway. With K9 damaged by the time winds, the regular universe remained inaccessible to him. Romana chose to stay with him in E-Space to help the enslaved Tharils release themselves from captivity.