As Managing Director of Harland & Wolff, the Belfast shipyard that built the Titanic, Thomas Andrews was responsible for the designing department at the shipyard and would have been aware of every aspect of the ship's design and construction. In a biography of Thomas Andrews published after his death author Shan Bullock wrote that as "surely none other did, he knew her inside and out, her every turn and art, the power and beauty of her...to the last rivet."

Thomas Andrews sailed aboard the Titanic, leading The Guarantee Group. Shan Bullock describes how with "his workmen he went about the boat all day long, putting things right and making note of every suggestion of an imperfection. Afterwards in his stateroom...he would sit for hours, making calculations and drawings for future use."

After the Titanic's collision with the iceberg Thomas Andrews was summoned from his stateroom by Captain Smith. On learning of the collision Andrews toured the ship to determine the damage caused by the iceberg. The extent of the damage and rate of water ingress into the hull must have been a terrific shock, with a sickening realisation that the Titanic would sink.

Back on the bridge, Andrews reported to Captain Smith on the severity of the situation.  Based on Andrews' assessment Captain Smith and his officers mustered the Titanic's passengers and began lowering the boats.  With insufficient lifeboat capacity for all on board both men will have known the terrible fate that would befall so many passengers and crew.  Both men would ultimately die in the sinking,

In the days following the sinking a number of sightings of Thomas Andrews were reported by survivors. Speaking at the US Senate Inquiry Stewardess Annie Robinson recalled that, half an hour after the collision, she had seen Captain Smith and Thomas Andrews returning from the mail room, and that she'd seen the rising water coming nearly to E-deck. Fifteen minutes later, seeing her without a lifebelt, Thomas Andrews implored her to put one on, saying "if you value your life put your belt on".

Bedroom Steward Henry Etches recalled at the US Senate Inquiry that he had seen Thomas Andrews at 12:20am on B-deck, asking if he'd woken all his passengers. They both then descended to C-deck where Thomas Andrews told Etches to wake the passengers, to make sure they opened their door, to tell them where to find their lifebelts and to help them in anyway he could. He last saw Thomas Andrews heading down to D-Deck.

The Sun newspaper in New York reported that "the last seen of him he was on deck A throwing steamer chairs overboard, some of which saved the lives of passengers struggling in the water" and also that "the third and fourth officers said that they saw him after the collision doing everything that was possible to assist in the rescue of the passengers without any regard to the danger in which he himself stood. Perhaps the most enduring image of Thomas Andrews, memorably reproduced in the 1958 film 'A Night to Remember' is a sighting by a steward of him alone in deep thought in the First Class Smoking Room.

His body, if recovered, was not identified. He is remembered on the family grave in Comber's Non-Subscribing Presbyterian Churchyard. The family grave is in obelisk form carved from poilshed granite, standing on a square base, rising in a tapered column and surmounted by a cruciform pediment with moulded cornice. A granite urn is mounted atop the pediment. Each side of the obelisk carries an inscription to members of the Andrews family. The northern face of the grave obelisk carries an inscription to Thomas Andrews Sr and his wife, Eliza, parents of Thomas Andrews Jr.

Their second son, Thomas Jr, is commemorated by an inscription on the western face of the grave obelisk. The inscription reads:

In Loving Memory Of Their Second Son Thomas, Born 7th February 1873, Lost at sea in the foundering of the S.S. "Titanic", 15th April 1912. Pure, Just, Generous, Affectionate and Heroic. "He gave his life that others might be saved"

Also commemorated on the family grave are Thomas and Eliza's other children and Eliza's parents, James and Eliza Pirrie.

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