RFC4 encodes the replication factor C subunit 4, an essential protein involved in DNA replication and repair. Biallelic pathogenic variants disrupting the C-terminal domain in RFC4 have recently been described to cause multisystemic disorder, associated with developmental delay, myopathy and neuropathy. Here we further characterize the less well understood neuromuscular manifestations in three patients with RFC4-related disease (RFC4-RD), two with early infantile onset and one with later onset. Patients P1 and P2, unrelated but with the same homozygous missense variant (c.841T>C:p.Cys281Arg), presented with early motor delays and regression, loss of head control before age 12 months, axial and proximal greater than distal weakness, progressive distal contractures, hearing loss, dysphagia, and failure to thrive. P2 developed respiratory failure requiring invasive mechanical ventilation (at 3 years) and second-degree atrioventricular heart block requiring a pacemaker (at 9 years). P3 has compound heterozygous variants: c.827dup:p.Val277Serfs*11 and c.957_962del:p.Leu319_Asp321delinsPhe and had later onset with childhood toe walking and frequent falls, abnormal gait (28 years), and loss of independent ambulation, respiratory insufficiency (needing nocturnal non-invasive ventilation), and hearing loss all with onset in the 4th decade of life. CK was mildly elevated in P3 but normal in P1-2. Muscle imaging and NCS/EMG in P1-3 showed diffuse involvement with both chronic myopathic and neurogenic features. Muscle biopsy revealed severe fiber atrophy and loss with fatty replacement in P2 and mild dystrophic changes in P3. Brain MRI in P1-3 was normal. This series characterizes the neuromuscular phenotype of RFC4-RD, highlighting severe and progressive disease associated with RFC4 Cys281Arg, and extending the phenotype to now also include a milder presentation in adulthood. Identification and characterization of additional patients is needed to fully understand the phenotypic spectrum and natural history of RFC4-RD.