The associations between different combinations of metabolic abnormalities and the risk of all and site-specific cancers remain unclear. We aimed to estimate the association and interplay between serum cholesterol, glycemic status and risk of cancer in the China Cardiometabolic Disease and Cancer Cohort (4C)-Study, a nation-wide, multicenter, prospective, population-based study. The investigation was performed in 137,884 participants during 2014-2016. Incident cancer was defined as the first occurrence of any type cancer of all sites during followup. After 510,164 person-years of follow-up, 1,710 were detected as incident cancer after exclusion of participants diagnosed as cancer within 6 months from baseline. A relatively low level of LDL cholesterol (<100 mg/dl) was related to a significant higher risk of incident cancer [1.20 (1.08-1.34); P=0.0007]. Diabetic individuals have a significantly higher risk of incident cancer, especially those with poorly glycemic control. Diabetic participants with both lower levels of LDL cholesterol and poorly glycemic control were at a higher risk of incident cancer [1.42 (1.10-1.81); P=0.006]. Our study showed a positive association of cancer risk with low-level LDL cholesterol and diabetes and found that participants with both lower levels of LDL cholesterol and poorly controlled diabetes had the higher risk of incident cancer, which indicates the compelling need of achieving glycemic control goal and maintaining appropriate LDL cholesterol levels.