ABSTRACT The cytochrome P450‐2D6 (CYP2D6) enzyme metabolizes ∼25% of common medications, yet homologous pseudogenes and copy number variants (CNVs) make interrogating the polymorphic CYP2D6 gene with short‐read sequencing challenging. Therefore, we developed a novel long‐read, full gene CYP2D6 single molecule real‐time (SMRT) sequencing method using the Pacific Biosciences platform. Long‐range PCR and CYP2D6 SMRT sequencing of 10 previously genotyped controls identified expected star (*) alleles, but also enabled suballele resolution, diplotype refinement, and discovery of novel alleles. Coupled with an optimized variant‐calling pipeline, CYP2D6 SMRT sequencing was highly reproducible as triplicate intra‐ and inter‐run nonreference genotype results were completely concordant. Importantly, targeted SMRT sequencing of upstream and downstream CYP2D6 gene copies characterized the duplicated allele in 15 control samples with CYP2D6 CNVs. The utility of CYP2D6 SMRT sequencing was further underscored by identifying the diplotypes of 14 samples with discordant or unclear CYP2D6 configurations from previous targeted genotyping, which again included suballele resolution, duplicated allele characterization, and discovery of a novel allele and tandem arrangement. Taken together, long‐read CYP2D6 SMRT sequencing is an innovative, reproducible, and validated method for full‐gene characterization, duplication allele‐specific analysis, and novel allele discovery, which will likely improve CYP2D6 metabolizer phenotype prediction for both research and clinical testing applications. Long‐read single molecule real‐time (SMRT) full gene sequencing of cytochrome P450‐2D6 (CYP2D6). Illustrated is the CYP2D6 gene and overview of amplicon preparation for SMRT sequencing.