Importance Smoking and obesity are associated with risk of hidradenitis suppurativa, and both are considered important environmental risk factors. However, a causal relationship remains unproven. Objective To primarily investigate the relationship between body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and smoking and HS, and secondarily to investigate potential relationships between 3 inflammatory diseases (psoriasis, inflammatory bowel disease [IBD], and systemic sclerosis [SSc]) and HS. Design, Setting, and Participants A mendelian randomization (MR) study conducted in 2024 on 5 exposure phenotypes (BMI, smoking, psoriasis, IBD, and SSc) on the outcome of phenotype HS was conducted. The MR analyses used large genetic White European cohorts from genome-wide association studies (GWAS) of each of the 6 phenotypes. Initial analyses were conducted May, 2024, and were updated in May, 2025. Exposure The 5 exposure phenotypes using predetermined genome-wide significant single-nucleotide variants as proxies for each particular exposure. Results The GWAS on HS included 4814 case patients and more than 1.2 million controls from Denmark, Iceland, Finland, the UK, and the US. The BMI GWAS involved 700 000 individuals from the UK Biobank and GIANT consortium. Smoking data were obtained from 1.23 million participants in an international consortium. The psoriasis GWAS analyzed 39 498 case patients and 286 769 controls from White European populations and a DNA genetic testing company. The IBD GWAS meta-analysis included 38 155 case patients and 48 485 controls from the International Inflammatory Bowel Disease (IBD) Genetics Consortium. The SSc GWAS included 9095 case patients and 17 584 controls from White European populations. Genetic correlations ( r g ) were found between HS and all exposure phenotypes except SSc (BMI: r g = 0.36, P &lt; .001; smoking: r g = 0.33, P &lt; .001; IBD: r g = 0.25, P &lt; .001; psoriasis: r g = 0.34, P &lt; .001; SSc: r g = 0.33, P = .22). MR analyses supported an effect of BMI on HS (β = 0.87; odds ratio [OR] per BMI unit, 1.20; 95% CI, 1.17-1.23; P &lt; .001) without signs of pleiotropy (slope: β = 0.91, P &lt; .001, P for intercept = .76). Smoking showed a significant causal estimate (β = 0.59, P &lt; .001), but results became inconclusive in subsequent sensitivity analyses. Among IBD, psoriasis, and SSc, results supported a causal effect of IBD on HS (β = 0.18, OR = 1.20; 95% CI, 1.15-1.24; P &lt; .001), without signs of pleiotropy. Conclusions and Relevance These findings indicate causal effects of IBD and increased BMI on the risk of HS. This information may help physicians inform patients about disease risk contributed by modifiable lifestyle behaviors, which can be beneficial for planning lifestyle interventions.