BACKGROUND: Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand, affecting up to 10% of the population, caused by compression of the median nerve at the wrist. Conventional observational epidemiological studies have demonstrated associations between CTS and elevated plasma insulin-like growth factor 1 (IGF-1), as well as several metabolic factors, such as obesity and type 2 diabetes (T2DM). METHODS: Here, we use two-sample univariable and multivariable Mendelian randomization to investigate causality in the relationships between IGF-1, metabolic factors related to IGF-1, and CTS. RESULTS: We replicate the result that increases in measures of obesity (body mass index (BMI), waist-hip ratio (WHR), and waist circumference (WC)) are causal for CTS, and show that the effect of elevated childhood BMI on increasing risk of CTS is mediated mostly by elevated adult BMI. Furthermore, we demonstrate that T2DM and raised fasting plasma glucose are also causal for CTS. Finally, we show that increased IGF-1 signalling is also causally related to CTS risk, and the effect is likely mediated by its effects on both BMI and T2DM. The IGF-1 pathway merits further investigation as a potential therapeutic target for CTS. CONCLUSION: We provide genetic epidemiological evidence to support obesity, T2DM, and elevated plasma IGF-1 concentrations playing a causal role in increasing the risk of CTS. These findings suggest that pharmacological management of the metabolic risk factors may also decrease the risk of CTS, with the IGF-1 pathway as a potential therapeutic target.