In the 1850s a steerage class ticket cost 8 shillings, several months' wages for a labourer, but business was brisk. In 1854 the City of Manchester made 5 voyages to Philadelphia alone, with over 500 passengers each trip. That same year disaster struck the company when the City of Glasgow disappeared en route to Philadelphia in March, and in September the City of Philadelphia ran aground on Cape Race, albeit with no loss of life.
In 1855 the Richardsons withdrew from the business after Inman violated their Quaker principles by leasing ships to France for use in the Crimean War. Inman dropped the Philadelphia service shortly after in favour of a New York service. By 1856 all the company's ships were screw-propelled in contrast to the more common paddle wheel steamers.
Until 1857 the Line ran a fortnightly service from Liverpool. That same year, following the collapse of the Collins Line, the Inman Line took its place carrying the US Mails. In 1860 they ran a weekly service, increasing in 1863 to three sailings every fortnight, and twice a week during summer in 1866. Their vessels gained a reputation for size, comfort and speed, the City of Paris making the trip from Cork to Halifax, Nova Scotia in under 7 days.
1870 saw another unfortunate incident, when the SS City of Boston departed Halifax for Liverpool and disappeared without trace.