The aims of this study were to estimate medical expenditures on human immunodeficiency virus (HIV) treatment and to identify significant associated variables. We performed a retrospective multi-centre study in the Canary Islands using a sample of 569 patients recruited at outpatient visits. The study examined demographic and clinical variables, health-related quality of life (HRQOL), and health care resources. Clinical data was obtained from medical records and patient interviews. Several empirical models for identifying the relationship between health care costs and independent variables were developed. The greatest expense came from pharmaceutical expenditure (82.1% of direct costs), while hospital costs only represented 4.6% of total expenditure. The data showed a statistically significant association between health care costs and the CD4 count of the previous year. HRQOL was also a significant variable. Therefore, CD4 cell count can be used to predict health care costs in patients. Policymakers could use this information to help guide their decisions in allocating limited health care resources to HIV treatments.