Twiggs's last command in the United States Army was as the commander of the Department of Texas from 1860 to 1861. He was actually ill for most of 1860, leaving then-lieutenant colonel Robert E. Lee as acting commander. Twiggs was able to reassume command in December 1860. When the state of Texas voted to seccede from the United States in February 1861, Twiggs, a strong believer in states' rights, found himself largely adrift, until he finally opted to surrender all U.S. property and munitions after his garrison in San Antonio was surrounded by 1,000 Texans led by Colonel Benjamin McCulloch. As his home-state of Georgia had already seceded, Twiggs commissioned as a major general in the C.S. Army in May 1861, but his illnesses prevented him from seeing combat. He died in 1862.
David E. Twiggs was unable to return to duty as Commander of the Department of Texas in 1860. Thus, when Texas voted to leave the Union in February 1861, it fell to Lt. Colonel Robert E. Lee to defend U.S. government property and munitions.