Objective: We aimed to describe the temporal variation in circulating lipid levels among patients with intracerebral hemorrhage (ICH) and investigate their association with ICH risk. Methods: This was a single-center, retrospective, longitudinal, case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a hospital-based clinical data registry. Piecewise linear mixed-effect random coefficient models were used to determine the significance of changes in serum lipid trends on ICH risk. Results: Two hundred twelve ICH cases and 301 control individuals were analyzed. Overall trends in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels differed between ICH cases and non-ICH controls (p 5 0.00001 and p 5 0.0092, respectively). Patients with ICH experience accelerated decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 and 24 months pre-ICH (TC: 229.25 mg/dL, p 5 0.001; LDL: 221.48 mg/dL, p 5 0.0038), which was not observed in non-ICH controls. Subgroup analysis confirmed that this phenomenon cannot be attributed to statin or alcohol exposure. Serum triglycerides and high-density lipoprotein trends did not differ between groups. Conclusions: Longitudinal lipid levels differ between ICH cases and non-ICH controls, most notably for a decline in serum TC and LDL levels within 6 months preceding primary ICH, independent of statin or alcohol use. These changes in serum TC and LDL trends suggest a biological pathway that precipitates ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.