Background: Cancer is associated with the dysregulation of serum serine levels, and tumor growth is supported by increased serine biosynthesis. This study aims to explore the association of serum serine levels with incident cancer risk in Chinese hypertensive adults. Materials and methods: 1391 patients with incident cancer and 1391 matched controls in terms of age, sex, and residence with cases in a 1 : 1 ratio were included in this nested case-control study. The serum serine concentrations were determined by liquid chromatography with tandem quadrupole mass spectrometry (LC-MS/MS) at the baseline. The associations of serum serine levels with the risk of overall, digestive system, non-digestive system, and lung cancers (the most common type) were assessed by conditional logistic regression. Results: When serum serine concentration was assessed as quartiles, a significantly higher risk of total cancer (OR = 1.32; 95% CI: 1.01-1.71; P = 0.038) was found in participants in the highest quartile (≥17.68 μg mL-1) compared with participants in the lowest quartile (<13.27 μg mL-1). Similar results were also observed for non-digestive system and lung cancers, but not for digestive system cancers. Significant associations of serum with overall cancer risk were found among all age subgroups, men, non-smokers, non-drinkers, and individuals with lower folic acid levels. Conclusion: High serum serine concentrations were associated with an increased risk of overall, non-digestive system, and lung cancers among Chinese hypertensive adult patients.