Genome‐wide expression studies of samples derived from individuals with autism spectrum disorder (ASD) and their unaffected siblings have been widely used to shed light on transcriptomic differences associated with this condition. Females have historically been under‐represented in ASD genomic studies. Emerging evidence from studies of structural genetic variants and peripheral biomarkers suggest that sex‐differences may exist in the biological correlates of ASD. Relatively few studies have explicitly examined whether sex‐differences exist in the transcriptomic signature of ASD. The present study quantified genome‐wide expression values by performing RNA sequencing on transformed lymphoblastoid cell lines and identified transcripts differentially expressed between same‐sex, proximal‐aged sibling pairs. We found that performing separate analyses for each sex improved our ability to detect ASD‐related transcriptomic differences; we observed a larger number of dysregulated genes within our smaller set of female samples (n = 12 sibling pairs), as compared with the set of male samples (n = 24 sibling pairs), with small, but statistically significant overlap between the sexes. Permutation‐based gene‐set analyses and weighted gene co‐expression network analyses also supported the idea that the transcriptomic signature of ASD may differ between males and females. We discuss our findings in the context of the relevant literature, underscoring the need for future ASD studies to explicitly account for differences between the sexes. Autism Res 2017, 10: 439–455. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.