Hyperhomocysteinaemia (HHcy) is associated with all-cause mortality in some disease states. However, the correlation between HHcy and the risk of mortality in the general population has rarely been researched. We aimed to evaluate the association between HHcy and all-cause and cause-specific mortality among adults in the USA. This study analysed data from the National Health and Nutrition Examination Survey database (1999–2002 survey cycle). A multivariable Cox regression model was built to evaluate the correlation between HHcy and all-cause and cause-specific mortality. Smooth curve fitting was used to analyse their dose-dependent relationship. A total of 8442 adults aged 18–70 years were included in this study. After a median follow-up period of 14·7 years, 1007 (11·9 %) deaths occurred including 197 CVD-related deaths, 255 cancer-related deaths and fifty-eight respiratory disease deaths. The participants with HHcy had a 93 % increased risk of all-cause mortality (hazard ratio (HR) 1·93; 95 % CI (1·48, 2·51)), 160 % increased risk of CVD mortality (HR 2·60; 95 % CI (1·52, 4·45)) and 82 % increased risk of cancer mortality (HR 1·82; 95 % CI (1·03, 3·21)) compared with those without HHcy. For unmeasured confounding, E-value analysis proved to be robust. In conclusion, HHcy was associated with high risk of all-cause and cause-specific (CVD, cancer) mortality among adults aged below 70 years.