Background　and　aims:　Evidence　is　increasingly　suggesting　that　shift　work　is　a　risk　factor　for　cardiometabolic　disease.　However,　the　causal　relationship　between　shift　work　and　cardiometabolic　disease　is　not　yet　fully　understood.　In　this　study,　we　employed　two-sample　Mendelian　randomization　(MR)　to　investigate　the　causal　relationship　between　shift　work　and　the　risk　of　cardiometabolic　outcomes.　Methods　and　results:　Genome-wide　association　study　(GWAS)　statistics　for　shift　work　were　obtained　from　the　UK　Biobank.　Mendelian　randomization　analyses　were　conducted　to　explore　the　causal　effects　of　shift　work　on　cardiometabolic　outcomes,　using　single-nucleotide　polymorphisms　(SNPs)　as　instrumental　variables.　The　results　suggested　a　causal　effect　between　shift　work　and　body　mass　index,　body　fat　percentage,　triglycerides,　high-density　lipoprotein,　type　2　diabetes,　hypertension,　and　cardiorespiratory　fitness.　After　correcting　for　multiple　tests,　only　body　mass　index　and　high-density　lipoprotein　showed　significant　associations.　No　causal　effects　were　found　between　shift　work　and　overweight,　obesity,　total　cholesterol,　low-density　lipoprotein,　fasting　glucose,　2-h　glucose,　fasting　insulin,　coronary　artery　disease,　myocardial　infarction,　heart　failure,　atrial　fibrillation,　or　ischemic　stroke.　Conclusion:　This　MR　study　provides　genetic　evidence　for　a　suggestive　causal　link　between　shift　work　and　certain　cardiometabolic　outcomes.　Our　research　may　have　the　significance　of　providing　insight　into　public　hygiene　to　improve　the　understanding　of　shift　work　and　cardiometabolic　disease　risk.　Further　experimental　studies　are　needed　to　confirm　our　findings.　(c)　2024　The　Author(s).　Published　by　Elsevier　B.V.　on　behalf　of　The　Italian　Diabetes　Society,　the　Italian　Society　for　the　Study　of　Atherosclerosis,　the　Italian　Society　of　Human　Nutrition　and　the　Department　of　Clinical　Medicine　and　Surgery,　Federico　II　University.　This　is　an　open　access　article　under　the　CC　BY-NC-ND　license　(http://creativecommons.org/licenses/by-nc-nd/4.0/).