The effects of exogenous nucleotides on the histamine hypersensitivity of pharmacologically beta-blocked mice were investigated. Female HLA-SW (ICR) mice, 27-29 gm, were injected intraperitoneally with 20 to 100 mug of propranolol 45 min before intraperitoneal challenge with 1 mg histamine. These animals had a mortality which averaged approximately 80%. At various time intervals before histamine, doses of from 0.5 to 12 mumoles of nucleotides were administered intravenously. Noncyclic nucleotides, adenosine, adenosine 5'-monophosphate (AMP), and guanosine 5'-monophosphate (GMP) showed clear, dose-response protection against histamine death of propranolol-treated mice when they were given 45 to 90 min before histamine. Cyclic AMP showed significant protection only when it was given at a dose of 8 mumoles 45 to 90 min before histamine, and lower or higher doses gave equivocal or no protection. Cyclic GMP WAS Not protective at any dose tested. Propranolol treatment also produced enhanced sensitivity to passive systemic anaphylaxis. Mice were passively sensitized by intraperitoneal injection of mouse anti-egg albumin antibody 6 hr before intravenous challenge with 0.5 mg egg albumin. The mortality from anaphylaxis in the group treated with 20 mug propranolol 45 min before antigen challenge increased to 83%, while that of the group not given propranolol was only 10%. Nucleotides were given intravenously 45 min before antigen challenge. The nucleotides that protected mice from death due to histamine challenge also protected them from death due to systemic anaphylaxis. These protective nucleotides were the same nucleotides that had been reported previously to be protective against Bordetella pertussis-induced hypersensitivity to histamine and anaphylaxis.