Objective: To investigate the causal relationship between risk factors and spontaneous pneumothorax using Mendelian randomization. Methods: Risk factors for spontaneous pneumothorax were identified through searches of English and Chinese databases. Single nucleotide polymorphism information was extracted from the GWAS database, with risk factor as exposure and spontaneous pneumothorax as outcome, and five methods, namely, inverse variance weighting, MR-Egger, weighted median, simple model and weighted model, were used to evaluate the causality between risk factors and spontaneous pneumothorax. Heterogeneity and leave-one-out tests were used for sensitivity analysis to evaluate the robustness of the causal relationship. Results: The search yielded 117 risk factors, and 50 risk factors for which genetic data were available were included. Height, COVID, lymphocytes, standing tall, snoring, exertion lung volume, squamous lung cancer, first second expiratory volume with exertion, and asthma were positively associated with SP, and hip circumference and exertion lung volume were negatively associated with SP. Chronic obstructive pulmonary disease and diaphragmatic hernia may be associated with SP. Conclusion: This study identified significant causal relationship between lymphocyte count, standing tall, asthma and spontaneous pneumothorax from genetic point of view, and provided basis for its prevention and treatment.