The role of interfacial contamination on antiphase domain boundary (APB) formation in GaAs grown epitaxially on Si(100) by metal-organic chemical vapor deposition was investigated. The pre-growth cleaning of the Si substrate was varied to affect the relative amount of residual surface contamination across the wafer. APB density in the as-grown GaAs film was examined with the aid of a selective APB etchant. The interfacial oxygen and carbon concentrations were determined using secondary ion mass spectrometry. It was found that the APB density increased significantly from 0.14 to 3.2 μm−1 between the center and the edge of the wafer. Over this distance, the integrated carbon concentration at the GaAs/Si interface increased by an order of magnitude and the integrated oxygen concentration, although two orders of magnitude lower than carbon, also increased by a factor of six. Analysis of the GaAs/Si interface with high-resolution transmission electron microscopy and high-angle annular dark field scanning transmission electron microscopy showed a direct association of APBs with amorphous interfacial particles. The particles are likely carbon-based, possibly SiC, and thus residual carbon contamination is believed to be the primary contributor to increased APB formation.