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Somatic mutations have been identified in adrenal tissues of unilateral primary aldosteronism (uPA). The spectrum of somatic mutations in uPAs was investigated using a customized and targeted next-generation sequencing (cNGS) approach. We also assessed whether cNGS or Sanger sequencing-identified mutations have an association with clinical outcomes in uPA. Adrenal tumoral tissues of uPA patients who underwent adrenalectomy were obtained. Conventional somatic mutation hotspots in 240 extracted DNA samples were initially screened using Sanger sequencing. A total of 75 Sanger-negative samples were further investigated by sequencing the entire coding regions of the known aldosterone-driver genes by our cNGS gene panel. Somatic mutations in aldosterone-driver genes were detected in 21 (28%) of these samples (8.8% of all samples), with 9 samples, including mutations in <i>CACNA1D</i> gene (12%), 5 in <i>CACNA1H</i> (6.6%), 3 in <i>ATP2B3</i> (4%), 2 in <i>CLCN2</i> (2.6%), 1 in <i>ATP1A1</i> (1.3%), and 1 in <i>CTNNB1</i> (1.3%). Via combined cNGS and Sanger sequencing aldosterone-driver gene mutations were detected in altogether 186 of our 240 (77.5%) uPA samples. The complete clinical success rate of patients containing cNGS-identified mutations was higher than those without mutations (odds ratio (OR) = 10.9; <i>p</i> = 0.012). Identification of somatic mutations with cNGS or Sanger sequencing may facilitate the prediction of complete clinical success after adrenalectomy in uPA patients.