Background: Solute carrier organic anion transporter family member 1B1 (SLCO1B1) mediates statin uptake into hepatocytes, the primary sites of cholesterol production. While the impact of SLCO1B1 variation on statin-associated muscle symptoms (SAMS) is well-documented, its role in LDL-C reduction remains understudied. This single-center, retrospective cohort study evaluated whether SLCO1B1 variation affects statin effectiveness in 213 adults. Methods: The SLCO1B1 variant rs4149056 (NM_006446.5:c.521T>C) was tested to categorize patients by their SLCO1B1 function: normal, decreased, or poor. The primary endpoint was percent change in LDL-C from baseline to follow-up (≥6 weeks post-statin initiation), with secondary endpoints of SAMS occurrence and statin adherence. Results: Overall, the average LDL-C decreased by 32% across all groups. No significant difference in LDL-C reduction was observed between SLCO1B1 phenotypes (p = 0.24). Conclusions: SLCO1B1 variation did not significantly affect LDL-C reduction, SAMS occurrence, or statin adherence. However, the retrospective design and limited adherence data in this study represent important limitations warranting prospective validation studies.