Understanding the causal impact that clinical risk factors have on healthcare-related costs is critical to evaluate healthcare interventions. Here, we used a genetically-informed design, Mendelian Randomization (MR), to infer the causal impact of 15 risk factors on annual total healthcare costs. We calculated healthcare costs for 373,160 participants from the FinnGen Study and replicated our results in 323,774 individuals from the United Kingdom and Netherlands. Robust causal effects were observed for waist circumference (WC), adult body mass index, and systolic blood pressure, in which a standard deviation increase corresponded to 22.78% [95% CI: 18.75-26.95], 13.64% [10.26-17.12], and 13.08% [8.84-17.48] increased healthcare costs, respectively. A lack of causal effects was observed for certain clinically relevant biomarkers, such as albumin, C-reactive protein, and vitamin D. Our results indicated that increased WC is a major contributor to annual total healthcare costs and more attention may be given to WC screening, surveillance, and mitigation.