Non-adherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication non-adherence. The visit-to-visit variability (VVV) of LDL-C may represent an opportunity to identify statin non-adherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center (BMC) Health Plan, seen at either BMC or its affiliated Community Health Centers, who were taking statins and had at least 3 LDL-C measurements between 2008 and 2011. The LDL-C VVV (defined by the within-patient standard deviation) was categorized into quintiles. Multivariable logistic regression models were generated with statin non-adherence (defined by the standard 80% pharmacy refill based medication possession ratio threshold) as the dependent variable. The proportion of statin non-adherence increased across quintiles of LDL-C VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL-C VVV had a strong positive association with statin non-adherence with an adjusted odds ratio of 3.4 (CI: 1.7–7.1) in the highest versus lowest quintile of LDL-C VVV. The age and gender adjusted model had poor discrimination [C-statistic 0.62 (CI: 0.57, 0.67)] while the final adjusted (age, gender, race, mean LDL-C) model demonstrated good discrimination [C-statistic 0.75 (CI: 0.71, 0.79)] between adherent and non-adherent patients. In conclusion, the VVV of LDL-C demonstrated a strong association with statin non-adherence in a clinic setting. Further, a VVV- of LDL-C based model has good discrimination characteristics for statin non-adherence. Research is needed to validate and generalize these findings to other populations and biomarkers.