BACKGROUND: Biologically active regulatory peptides are the drugs of new type that act selectively on targets, with having no significant side effects. AIM: The aim of the study was to study the potential effect of peptide preparations Cortexin and Semax on the resistance of the rat organism to the cold stress factor in the model of cold stress maladaptation. MATERIALS AND METHODS: White outbred male rats were injected intraperitoneally twice daily with placebo (n = 30), Cortexin 5 mg/kg (n = 30) or Semax 0.3 mg/kg (n = 30). Three days after the start of the injection course, the cold-stress effect was simulated in the climate chamber (Feutron, Germany) by cooling the air to 5C at a relative humidity of 7580%. RESULTS: The use of RP significantly increased the duration of the rectal temperature plateau-period within 35C (moderate hypothermia): in animals of the Cortexin group from 10 days to 12 days, and in animals of the Semax group, from 10 to 14 days. Cortexin demonstrated moderate immunomodulatory properties, and Semax had a more pronounced immunomodulatory effect. Both preparations showed a stress-protective effect. The use of regulatory peptides provided to delay the decrease in the rat general motor activity and exploratory behavior which develops under the influence of a simulated cold-stress factor. A slower rate of decrease in the swimming time of rats under the influence of regulatory peptides was registrated. CONCLUSIONS: The meteoadaptogenic, stress-protective and nootropic effects of the regulatory peptides Cortexin and Semax were confirmed in rats on the model of cold-stress maladaptation.