High-risk upper tract urothelial carcinoma (UTUC) has been associated with poor survival outcomes. The authors evaluated the role of neoadjuvant chemotherapy in high-risk cases prior to radical nephroureterectomy (RNU) in terms of pathological stage of the final surgical specimen. A total of 240 patients were included. Neoadjuvant chemotherapy was offered to cases with biopsy proven high-grade disease and a visible lesion on imaging (group A). No patients had undergone endoscopic ablation prior to RNU. This was compared to patients with high-grade disease but no visible lesion on imaging, who directly underwent extirpative surgery (group B). There were 32 cases in group A and 208 in group B. All patients underwent RNU and standard regional lymphadenopathy and removal of any other suspicious lesions. Significantly lower pathological stage was noted in the study group A compared to group B. Of the 32 cases, 53.1% received combination gemcitabine and cisplatin, 37.5% received dose-dense methotrexate, vinblastine, doxorubicin and cisplatin and 9% received gemcitabine alone, gemcitabine with docetaxel or gemcitabine with cisplatin and bevacizumab. All patients completed a median of four cycles (range 3-6). The overall prevalence of pT2 disease or higher was significantly lower in group A (37.5%) compared to group B (59.6%). All patients who were high-grade on preoperative biopsy remained high-grade in both groups post RNU. In patients who had lymph node dissection, there was no significant difference in pathological nodal stage. There was a 46.5% reduction in the prevalence of pT3 disease or higher in the study group without preoperative clinically node positive or low volume metastatic disease. A 9.4% complete remission rate was observed in group A. The group A patients were all studied in recent years precluding five and ten years’ survival data comparison. The study supports the use of neoadjuvant chemotherapy in high risk UTUC prior to radical surgery as it leads to significant downstaging of the tumour.