Objective The 'LESS-CHRON criteria' (List of Evidence-Based Deprescribing for Chronic Patients criteria) is a newly created tool with 27 criteria to guide deprescribing. It was developed using a Delphi methodology. Each criterion consists of drugs and their indications, conditions under which deprescribing would be considered, a health variable to be monitored after deprescribing and a follow-up period. The aim of our study was to evaluate the reliability of the LESS-CHRON criteria in a population of patients with multimorbidity to determine the possible usefulness of this tool in clinical practice. Methods We selected chronic patients with multimorbidity from an internal medicine unit who were older than 80 years old and were alive at the time of the study. To determine interobserver reliability, each professional (internist or hospital pharmacy specialist) applied the questionnaire under the same conditions and with the same resources. To determine intraobserver reliability, each health professional applied the tool at baseline and 2 months later. We measured interobserver and intraobserver reliability using the kappa coefficient. The proportion of overall agreement was also determined. Results We obtained a moderate overall kappa (=0.46, 95% CI 0.36 to 0.55) for interobserver reliability, and good (=0.65, 95% CI 0.57 to 0.78) and moderate (=0.59, 95% CI 0.49 to 0.74) values for intraobserver reliability for the internist and pharmacist, respectively. The proportion of overall agreement was very high: 92% (range: 62%-100%) for the interobserver, and 94% (80%-100%) and 93% (63%-100%) for the internist and pharmacist, respectively. Conclusions The LESS-CHRON criteria shows early promise as a reliable method to help guide deprescribing in patients with multimorbidity. Further, more complete testing with a larger sample of prescribers is needed.