<p>Neuroblastoma (NB) is a common pediatric malignant tumor, accounting for approximately 13% of childhood cancer-related deaths. It has a poor prognosis, and its pathogenesis and genetic characteristics remain complex. Although recent studies have suggested a potential association between immune cells and NB, the causal relationship remains unclear. In this study, we utilized genome-wide association studies (GWAS) summary statistics of 731 immune traits (<i>n</i> = 3757) and three NB subtypes: MYCN-amplified NB (<i>n</i> = 5369), 11q-deletion NB (<i>n</i> = 5222), and 1p-deletion NB (<i>n</i> = 5178). We conducted Mendelian randomization (MR) analyses to assess the causal relationship between immune cells (exposure) and these NB subtypes (outcome). After false discovery rate (FDR) correction, neither 11q-deletion NB nor 1p-deletion NB showed significant associations with immunophenotypes. However, and only one immunophenotype was positively correlated with the risk of MYCN-amplified NB: HLA DR on monocyte (OR: 1.754 [95% CI = 1.288 to 2.390], <i>p</i> = 3.6 × 10^–4, <i>q</i> value = 0.194). Reverse MR analysis did not support a causal effect of MYCN-amplified NB on HLA DR expression in monocytes. Sensitivity analyses further confirmed the stability and reliability of these findings. Our MR study provides strong evidence for a causal relationship between&#xa0;HLA DR on monocyte&#xa0;and MYCN-amplified NB, suggesting that elevated HLA DR expression may be a risk factor for this aggressive subtype. These findings could inform clinical decision-making regarding prognosis and treatment strategies for MYCN-amplified NB and may also identify potential therapeutic targets.</p>