Urticaria is a prevalent autoimmune skin disorder characterized by localized wheals and intense pruritus, significantly impairing the quality of life for affected individuals. Previous research has indicated that plasma proteins may contribute to the pathogenesis of urticaria. However, these findings do not establish a causal relationship. To address this gap, we conducted a large-scale Mendelian randomization(MR) study of the plasma proteome. In this study, we employed a two-sample, bidirectional Mendelian randomization approach to evaluate the causal relationship between the plasma proteome and urticaria. Utilizing large, publicly available genome-wide association studies, we examined the association of 4907 plasma proteins with the risk of developing urticaria. To assess heterogeneity and horizontal pleiotropy, we applied Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Furthermore, a sensitivity analysis was conducted to evaluate the influence of individual single nucleotide polymorphisms on the MR findings. Additionally, we performed enrichment analysis and GeneMANIA analysis to identify and annotate the functions of the selected plasma protein genes and to determine associated genetic factors. In this study, we examined 4,907 plasma proteomes as exposures and urticaria as the outcome. The findings revealed significant associations for several proteins, including CHCHD10, HBB, GZMB, LILRB2, MICB, IL21, FTMT, JPH4, and ISOC1 with the risk of urticaria. Specifically, three plasma protein phenotypes were identified as protective factors: GZMB (odds ratio [OR] = 0.76, 95% confidence interval [CI] 0.65-0.88, P <
0.001), MICB (OR = 0.82, 95% CI 0.76-0.89, P <
0.001), and FTMT (OR = 0.79, 95% CI 0.74-0.83, P <
0.001). Conversely, other plasma protein phenotypes were identified as risk factors for urticaria: CHCHD10 (OR = 2.68, 95% CI 1.54-4.67, P <
0.001), HBB (OR = 1.21, 95% CI 1.08-1.36, P = 0.001), LILRB2 (OR = 1.08, 95% CI 1.04-1.12, P <
0.001), IL21 (OR = 1.19, 95% CI 1.08-1.31, P <
0.001), JPH4 (OR = 1.30, 95% CI 1.13-1.50, P <
0.001), and ISOC1 (OR = 1.18, 95% CI 1.07-1.30, P <
0.001). Additionally, reverse Mendelian randomization analysis indicated that urticaria was a risk factor for ISOC1 (OR = 0.93, 95% CI 0.86-0.99, P = 0.03). We identified a bidirectional causal relationship between ISOC1 and urticaria. This study successfully elucidated the causal relationship between plasma protein phenotypes and urticaria, contributing valuable information for understanding the pathophysiology of the condition. Furthermore, it offers new genetic insights that may inform the identification of potential therapeutic targets for urticaria.