Shelley had to hide from bill collectors through the fall and winter, and apart from various clandestine assignations, Mary saw very little of him. Early in 1815 she began an affair with a lawyer, friend, and creditor, Thomas Jefferson Hogg. Shelley, who had become involved with Claire, approved of the liaison. On February 22, 1815, while Shelley was away, Mary give birth prematurely to her first child, a girl, who died twelve days later, shortly after Hogg had helped Mary and the infant move to a different apartment. Mary became pregnant again almost immediately by Shelley; her second child, William, was born on January 24, 1816.

In the spring of 1816 Mary, Shelley, William, and Claire set up house near Lake Geneva, below the Villa Diodati, which was occupied by the poet Lord Byron, with whom Claire had had a brief affair earlier in the year, and whose child she eventually bore. It was a rainy summer, and they spent long nights with Byron and Polidori, his doctor, talking about the supernatural and science, and challenging one another to write ghost stories. One such conversation in mid-June—mostly about galvanism being used to reanimate a corpse—stretched almost until dawn, and when Mary finally got to bed, she dreamed a student built a human being and—as she put it—woke him up with machinery. The dream inspired her first novel, Frankenstein. Its composition was interrupted by a move back to England, intermittent sickness from a third pregnancy, and the suicides of her half sister Fanny and of Harriet Shelley, in October and November, respectively. Harriet, also pregnant by Shelley, drowned herself in the Serpentine.

Mary married Shelley on December 30, 1816. Five months later she finished Frankenstein, and on September 2, 1817, she gave birth to her third child, Clara, and published Journal of a Six Weeks’ Tour, a travel book. Frankenstein was published on January 1, 1818, and immediately became a bestseller, although she never made much money from it.

Several months later the Shelleys moved permanently to Italy. On September 24, 1818, Clara died in Venice, of an illness that originated with a tooth infection; on June 7, 1819, William died in Rome of malaria while Mary was expecting her fourth child. Consumed by feelings of hopelessness, she wrote Matilda, a melodramatic novel whose theme is father-daughter incest. Her father, who, having become destitute, had begun to beg money from her, advised her not to publish it, and she agreed. On November 12, 1819, she gave birth to a son, Percy, in Florence. The following year she began work on a medieval Italian romance, Valperga, intending to donate royalties to her father, and became pregnant for the fifth time. She suffered a miscarriage in June 1821.