tert-butyllithium is a pyrophoric substance, meaning that it spontaneously ignites on exposure to air. Air-free techniques are important so as to prevent this compound from reacting violently with oxygen and moisture:
:t-BuLi + O → t-BuOOLi
:t-BuLi + HO → t-BuH + LiOH
The solvents used in common commercial preparations are themselves flammable. While it is possible to work with this compound using cannula transfer, traces of tert-butyllithium at the tip of the needle or cannula may ignite and clog the cannula with lithium salts. While some researchers take this "pilot light" effect as a sign that the product is "fresh" and has not degraded due to time or improper storage/handling, others prefer to enclose the needle tip or cannula in a short glass tube, which is flushed with an inert gas and sealed at each end with septa. Serious laboratory accidents involving tert-butyllithium have occurred. For example, in 2008 a staff research assistant, Sheharbano Sangji, in the lab of Patrick Harran at the University of California, Los Angeles, died after being severely burned by a fire ignited by tert-butyllithium.
Large-scale reactions may lead to runaway reactions, fires, and explosions when tert-butyllithium is mixed with ethers such as diethyl ether, and tetrahydrofuran. The use of hydrocarbon solvents may be preferred.