The effect of human serum on the immunological and biological activity of thyrotropin releasing hormone (TRH) has been studied. Inactivation of TRH immunological activity was rapid, occurring at a rate of 6.2%/min when a large quantity of TRH (2 μg/ml) was added to normal serum. Smaller quantities of TRH were more rapidly destroyed and significant TRH loss occurred in serum diluted 1:64. The temperature optimum of the reaction was 37 C. Serum that had been heated at 60 C for 30 min or exposed to pH 3.0 or 10.0 did not inactivate TRH. TRH biological activity was destroyed by incubation of TRH in serum at 37 C whereas it was preserved after incubation of TRH in serum at 60 C. Incubation of TRH—serum mixtures at 60 C after 37 C incubation resulted in recovery of some TRH immunological and biological activity. These results show that serum contains a heat, acid and alkali labile substance (s) which inactivates the biological and immunological activity of TRH in a similar manner. (Endocrinology91: 657, 1972)