Background: RMC is a highly aggressive renal cell carcinoma (RCC) with poor prognosis and variable response to chemotherapy. It is often treated with cytotoxic regimens used for collecting duct carcinoma (CDC) and upper tract urothelial carcinoma (UTUC). We analyzed the transcriptomic profile of RMC samples and compared it with that of CDC, UTUC, clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). Methods: RNA sequencing (RNA-seq) was performed in primary tumor tissues from treatment-naïve patients with RMC (n = 11), CDC (n = 9), and UTUC (n = 22). We compared these profiles to ccRCC, pRCC, and chRCC samples (n = 20 each) randomly selected from The Cancer Genome Atlas (TCGA). Gene ontology (GO) analysis was performed using DAVID. In vitro cell proliferation was assessed using the MTT assay. Results: Unsupervised hierarchical clustering and principal component analyses showed that 9/11 RMC samples formed a distinct cluster while 2 samples overlapped with CDC (p = 0.0003). There was no overlap between RMC and UTUC, ccRCC, pRCC, or chRCC. Five patients with RMC showed at least partial response to subsequent chemotherapy (4/5 received a paclitaxel-based regimen) and their pre-treatment samples demonstrated upregulation of 62 genes (FDR < 0.05) compared with the other patients. GO analysis revealed that these genes are associated with transmembrane transport pathways (enrichment score 3.87). The most upregulated gene ( > 3-fold) was guanine deaminase (GDA), a regulator of microtubule assembly normally expressed in human kidney collecting ducts. In vitro siRNA knockdown of GDA in the paclitaxel-sensitive RCC cell lines HCR-59 and UOK-146 conferred resistance to paclitaxel but not to drugs that do not target microtubules such as gemcitabine, doxorubicin, or platinum agents. Conclusions: RMC displays a unique transcriptomic signature that is closer to CDC than to UTUC or to other RCC subtypes. RMC tumors more likely to respond to chemotherapy show upregulation of genes such as GDA. Our results provide the first evidence that GDA may be a biomarker of response to microtubule-targeting agents in RMC.