OBJECTIVES: The aim of this study is to (i) review the methodological quality of pharmacoeconomic evaluations of orphan and expensive drugs that applied for reimbursement in The Netherlands, and (ii) explore essential criteria in the reimbursement recommendations made by The Dutch National Healthcare Institute (ZINL). METHODS: Data were extracted from pharmacoeconomic reports published by ZINL between 1 January 2006 and 31 December 2013 using a data extraction form. Compliance to pharmacoeconomic guidelines was determined by evaluating deviations in the pharmacoeconomic reports from the list of provided items in the guidelines. Multiple variables (i.e. drug safety, efficacy, therapeutic value, and cost-effectiveness) were investigated regarding their influence on the reimbursement recommendation by performing the Pearson's Chi-squared test, Kolmogorov-Smirnov test, and Wilcoxon rank sum test.  RESULTS: In total, 53 pharmacoeconomic evaluations were included in this study. Of these, 16 concerned orphan drugs, while 37 evaluated high cost- drugs. Of the 53 pharmaceutical compounds evaluated in this study, 39 (73.6%) received a positive reimbursement advice, 11 (20.8%) received a negative reimbursement advice, and 3 drugs were not assessed for reimbursement through either the outpatient reimbursement system nor the intramural high cost reimbursement system (5.7%). In total, 277 deviations from the pharmacoeconomic guidelines were observed, but no single item was found to have a statistically significant effect on the reimbursement recommendation. In contrast to drug safety and cost-effectiveness outcomes, both drug efficacy and therapeutic value showed to have statistically significant impact on the reimbursement decision. CONCLUSIONS: In The Netherlands, drug efficacy and therapeutic value can be considered as essential criteria in the reimbursement decision of orphan and expensive pharmaceuticals, resulting in a reimbursement system being centered on clinical value. Even though cost-effectiveness does not have a significant impact on the decision, compliance in the reimbursement dossiers by manufacturers to the Dutch Guidelines for Pharmacoeconomic research can be further improved.