Sarno's most notable (and controversial) achievement is the development, diagnosis and treatment of TMS, which is not recognized by mainstream medical science. According to Sarno, TMS is a psychosomatic illness causing chronic back, neck, and limb pain which is not relieved by standard medical treatments. He includes other ailments, such as GI problems, dermatological disorders and repetitive-strain injuries as TMS related. Sarno states that he has successfully treated over ten thousand patients at the Rusk Institute by educating them on his beliefs of a psychological and emotional basis to their pain and symptoms. Sarno's theory is, in part, that the pain or GI symptoms are an unconscious "distraction" to aid in the repression of deep unconscious emotional issues. Sarno believes that when patients think about what may be upsetting them in their unconscious they can defeat their minds strategy to repress these powerful emotions in this manner, the symptoms are seen for what they are and the symptoms then serve no purpose, and they go away. Supporters of Sarno's work hypothesize an inherent difficulty in performing the clinical trials needed to prove or disprove the diagnosis, since it is difficult to use clinical trials with psychosomatic illntesses.

Sarno wrote about his experience in this area in his first book on TMS, Mind Over Back Pain. His second book, Healing Back Pain: The Mind-Body Connection, has sold over 150,000 copies. Sarno's most recent book featured chapters by six other doctors and addressing the entire spectrum of psychosomatic disorders and the history of psychosomatic medicine.

Sarno's books describe two follow-up surveys of his TMS patients. The first in 1982 interviewed 177 patients selected randomly from those Sarno treated in the preceding three years. 76% stated that they were leading normal and effectively pain-free lives. A second follow-up study in 1987 restricted the population surveyed to those with herniated discs identified on CT-scans, and 88% of the 109 randomly selected patients stated that they were free of pain one to three years after TMS treatment.

In 2007, David Schechter (a medical doctor and former student and research assistant of Sarno's) published a peer-reviewed study of TMS treatment showing a 54% success rate for chronic back pain. The average pain duration for the study's patients was 9 years. In terms of statistical significance and success rate, the study outperformed similar studies of other psychological interventions for chronic back pain.

Notable patients of Sarno include radio personality Howard Stern, actress Anne Bancroft, 20/20 co-anchor John Stossel and television writer Janette Barber. All four have praised Sarno and his work highly. Stern dedicated his first book in part to Sarno.