The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multi-gene panel including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T) and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of £378 (US$491), and a QALY gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01) and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)) but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels.