Cochlear implantation is currently the treatment of choice for children with severe to profound hearing impairment. However, the outcomes with cochlear implants (CIs) vary significantly among recipients. The purpose of the present study is to identify the genetic determinants of poor CI outcomes. Twelve children with poor CI outcomes (the “cases”) and 30 “matched controls” with good CI outcomes were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 129 known deafness genes. Audiological features, imaging findings, and auditory/speech performance with CIs were then correlated to the genetic diagnoses. We identified genetic variants which are associated with poor CI outcomes in 7 (58%) of the 12 cases; 4 cases had bi-allelic PCDH15 pathogenic mutations and 3 cases were homozygous for the DFNB59 p.G292R variant. Mutations in the WFS1, GJB3, ESRRB, LRTOMT, MYO3A, and POU3F4 genes were detected in 7 (23%) of the 30 matched controls. The allele frequencies of PCDH15 and DFNB59 variants were significantly higher in the cases than in the matched controls (both P < 0.001). In the 7 CI recipients with PCDH15 or DFNB59 variants, otoacoustic emissions were absent in both ears, and imaging findings were normal in all 7 implanted ears. PCDH15 or DFNB59 variants are associated with poor CI performance, yet children with PCDH15 or DFNB59 variants might show clinical features indistinguishable from those of other typical pediatric CI recipients. Accordingly, genetic examination is indicated in all CI candidates before operation.