Liddle published 223 research papers throughout his career. Much of his research focused on the hypothalamic–pituitary–adrenal axis and diseases that can affect it. He was the first to show that Cushing's disease was caused primarily by an abnormality in the anterior pituitary rather than the adrenal glands. He also described Liddle's syndrome, a genetic syndrome causing high blood pressure. Liddle developed the dexamethasone suppression test for assessing adrenal function and the metyrapone test for pituitary reserve. He discovered a method for measuring aldosterone levels in urine and pioneered the use of spironolactone in the treatment of high blood pressure. He also discovered that certain cancers, especially of the lungs, can secrete ACTH, producing a paraneoplastic Cushing's syndrome. Based on his research into paraneoplastic syndromes, he coined the term "ectopic hormone secretion".
