Unmet health needs in patients with rare diseases require the introduction of new technologies and procedures. This study reviewed all available cost-effectiveness analyses (CEAs) of health interventions in rare diseases in Spain. A literature search of economic evaluations was conducted in ICER-eSalud, a database that includes data from CEAs published in Spain obtained from Spanish (Agencias Españolas de Evaluación de Tecnologías Sanitarias, IBECS, PharmacoEconomics Spanish Research Articles) and international (Pubmed, Science Direct, Centre for Reviews and Dissemination) databases. Studies published between 2002 and 2017 in which the disease is defined as rare according to Orphanet criteria (affecting < 5 people per 10,000 in Europe) were included. Thirty-nine studies of health interventions in 34 rare diseases met the inclusion criteria. Of these, 17 (44%) evaluated pharmaceutical products, 15 (38%) public health programs, 5 (13%) surgical procedures, and 2 (5%) the delivery of care. The most frequent therapeutic areas were oncology, metabolic disorders and haematology. A total of 133 incremental cost-effectiveness ratios (ICERs) were found, of which 61 (46%) were expressed as cost per quality-adjusted life year (QALY) and 72 (54%) as life-year gained (LYG). The median ICERs were €27,386/QALY (range 6,083-6,847,284), €25,010/QALY (301-81,296), €17,745/QALY (8,330-202,646) and €9,021/QALY (3,446-12,865) for pharmaceutical products, public health programs, delivery of care and surgical procedures, respectively. Approximately 54% of the interventions were cost-effective at a threshold of €21,000/QALY. Twenty-one percent of the ICERs showed an intervention that was dominant due to greater utility and lower costs, while the intervention was dominated in 5%. The median ICERs, expressed as LYG, varied from €14,116/LYG (776-501,868) for delivery of care to €21,789/LYG (5,149-219,665) for public health programs. More than half of rare disease interventions were cost-effective in Spain. However, the results may vary greatly according to the type of technology and the disease concerned.