Objective Higher body mass index (BMI) increases the risk of meniscus injury and knee osteoarthritis (OA). However, it is unknown if and how obesity affects meniscus biology. We analyzed transcriptome-wide gene expression profiles of injured human menisci to test the hypothesis that meniscal gene expression signatures relate to patient BMI. Methods Meniscus samples were obtained from patients undergoing arthroscopic partial meniscectomy. Transcriptome-wide analysis of gene expression followed by validation of selected transcripts by QuantiGene Plex assay was performed. Correlations of gene expression with BMI and relative fold changes (≥1.5-fold) in 3 BMI categories (lean [BMI 18.5-24.9 kg/m2], overweight [BMI 25.0-29.9 kg/m2], and obese [BMI >30.0 kg/m2]) were analyzed, and integrated functional classifications were probed computationally. Results The obese versus overweight comparison resulted in the largest set of differences (565 transcripts) followed by obese versus lean (280 transcripts) and overweight versus lean (125 transcripts). Biologic reproducibility was confirmed by cluster analysis of expressed transcripts. Differentially regulated transcripts represented important functional classifications. Transcripts associated with oxygen transport, calcium ion binding, and cell homeostasis were elevated with BMI, while those related to extracellular matrix deposition, cell migration, and glucosamine metabolic processes were repressed. While these functional classifications may play key roles in cartilage/meniscus homeostasis, failure of extracellular matrix deposition and increase in calcium ion binding likely contribute to OA development following meniscal injury. Conclusion Our results indicate greater differences in gene expression between obese and overweight groups than between overweight and lean groups. This may indicate that there is a weight threshold at which injured meniscus responds severely to increased BMI. BMI-related changes in gene expression present a plausible explanation for the role of meniscal injury in OA development among obese patients.