Objective: There are differences between countries regarding data requirements for orphan drug evaluation and it is also unknown which criteria might determine the price and reimbursement decision. This study aimed to identify the key criteria for price and reimbursement of orphan drugs in Spain, approved by the European Commission, between January 2012 and June 2018. Method: A descriptive analysis of the orphan drugs and its characteristics was performed. Outcomes criteria assessed were: therapeutic area, existence of alternative treatment, rarity of the disease, clinical trial outcomes and therapeutic positioning report assessment. Hypotheses for each variable regarding Spanish pricing and reimbursement were made and tested with two regression analyses. Results: Out of 78 orphan drugs approved by the European Commission, 82.1% asked pricing and reimbursement in Spain. From this, 43.8% had pricing and reimbursement approved and 20.3% rejected. Mean time from Spanish marketing authorisation approval to pricing and reimbursement approval was 12.1 ± 5.1 months. Having a positive therapeutic positioning report and no therapeutic alternatives would be associated with a positive pricing and reimbursement in Spain. Conclusions: It remains challenging to establish which are the driving criteria for pricing and reimbursement approval of orphan drugs in Spain. Further research should be done including other variables that might influence the pricing and reimbursement final decision in Spain.