The reference change value (RCV) is calculated by combining the within-subject biological variation (CVI) and local analytical variation (CVA). These calculations do not account for the variation seen in preanalytical conditions in routine practice or CVI in patients presenting for treatment. As a result, the RCVs may not reflect routine practice or align with clinicians' experiences. We propose a novel RCV approach based on routine patient data that is potentially more clinically relevant. This study used the refineR algorithm to determine RCVs using serial patient data extracted from a local Laboratory Information System (LIS). The model was applied to biomarkers with a range of result ratio distributions varying from normal to log-normal. Results were compared against conventional formula-based RCVs using CVI estimates from a state-of-the-art biological variation study. Monte Carlo simulations were also used to validate the LIS data approach. The RCVs estimated from LIS data were: 11-deoxycortisol (men): -70%/+196%, 17-hydroxyprogesterone (men): -49%/+100%, albumin: -10%/+11%, androstenedione (men): -47%/+96%, cortisol (men): -54%/+51%, cortisone (men): -32%/+51%, creatinine: -16%/+14%, phosphate (women): -23%/+29%, phosphate (men): -27%/+29%, testosterone (men): -38%/+60%. The formula-based RCV estimates showed similar but slightly lower results, and the Monte Carlo simulations confirmed the applicability of the new approach. RCVs may be estimated from patient results without prior assumptions about the shape of the ratios between serial results. Laboratories can determine RCVs based on local practice and population.