Acute urticaria (AU) and Lyme borreliosis (LB) are known to alter the transcriptional profile of blood cells. The nature of changes in the transcriptional activity of genes of the innate and adaptive immune system in the peripheral blood in patients with comorbid AU and LB is unknown. In our study, we applied a pathway-specific PCR array (Human Innate & Adaptive Immune Responses RT2 Profiler PCR Array, QIAGEN, Germany) to detect and verify the innate and adaptive immune responses of pathway-focused genes expression in the blood of patients with a comorbid course of these pathologies. It was found that in patients with comorbid AU and Lyme disease, transcriptional induction of a number of genes of the innate immune system in PBMC was observed, in particular: TLR2, NOD2, NLRP3, APCS, complement component 3 (C3), CD14, CD86 compared with patients suffering from acute urticaria. These changes were accompanied by an increased transcriptional activity of systemic proinflammatory cytokines IL1B, IL6, IFNG and its receptor IFNGR1, TNF, ligands, and chemokine receptors CXCL10, CXCR3, CCR5, tyrosine kinase JAK2 and transcription factors STAT1 and TBX21. At the same time, the comorbid course of acute urticaria and Lyme disease led to the repression of the transcriptional activity of the CD80, IL4, and CXCL8 genes. The comorbid course of acute urticaria and Lyme borreliosis is accompanied by activation of the transcriptional activity of genes of the innate immune system and proinflammatory cytokines.