The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage tracing back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly due to genomic changes in subclade IIb MPXV. Key genomic changes occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and often dismissed as uninformative. Using highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including *OPG153*, *OPG204*, and *OPG208*, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We propose that genomic studies focusing on phenotypic MPXV differences should consider LCR variability. The study provides a comprehensive genomic characterization of LCRs during the mpox outbreak. Our analysis establishes that LCRs exhibit a non-random distribution across the genome and display higher entropy compared to SNPs. Importantly, our findings highlight three specific gene candidates that warrant further investigation in relation to transmissibility and/or adaptation. As a result, we propose a focused examination of LCR variability in future MPXV genomic analyses. The distinctive characteristics observed in LCRs emphasize their potential significance in understanding the dynamics of the currently circulating viral clades and suggest promising avenues for targeted research.The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage tracing back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly due to genomic changes in subclade IIb MPXV. Key genomic changes occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and often dismissed as uninformative. Using highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including *OPG153*, *OPG204*, and *OPG208*, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We propose that genomic studies focusing on phenotypic MPXV differences should consider LCR variability. The study provides a comprehensive genomic characterization of LCRs during the mpox outbreak. Our analysis establishes that LCRs exhibit a non-random distribution across the genome and display higher entropy compared to SNPs. Importantly, our findings highlight three specific gene candidates that warrant further investigation in relation to transmissibility and/or adaptation. As a result, we propose a focused examination of LCR variability in future MPXV genomic analyses. The distinctive characteristics observed in LCRs emphasize their potential significance in understanding the dynamics of the currently circulating viral clades and suggest promising avenues for targeted research.