Aim: Evaluate the cost–effectiveness of combinatorial pharmacogenomic (PGx) testing, versus treatment as usual (TAU), to guide treatment for patients with depression, from the Canadian public healthcare system perspective. Materials & methods: Clinical and economic data associated with depression were extracted from published literature. Clinical (quality-adjusted life years; QALYs) and economic (incremental cost–effectiveness ratio) outcomes were modeled using combinatorial PGx and TAU treatment strategies across a 5-year time horizon. Results: With the combinatorial PGx strategy to guide treatment, patients were projected to gain 0.14–0.19 QALYs versus TAU. Accounting for test price, combinatorial PGx saved CAD 1,687–3,056 versus TAU. Incremental cost–effectiveness ratios ranged from -11,861to−16,124/QALY gained. Conclusion: Combinatorial PGx testing was more efficacious and less costly compared with the TAU for depression. </jats:p