The objective was to define the relationship between histopathological changes after pre-operative chemo-radiotherapy (CRT) and clinical outcome following tri-modality therapy in patients with superior sulcus tumours. A retrospective analysis of tumour material was performed in a series of 46 patients who received tri-modality therapy between 1997 and 2007. Median follow-up was 34 months (5-154). Pathological complete response (pCR) was present in 20/46 tumours (43 %). The most common RECIST score after CRT in patients with pCR was a partial response (PR; 10/17, three unknown), whereas in patients without a pCR, stable disease was the most common (22/26) (p = 0.002). In 26 specimens with residual tumour, this was mainly located in the periphery of the lesion rather than the centre (Spearman's correlation = 0.67, p < 0.001). Prognosis was significantly better after a pCR compared to residual tumour (70 % 5-year overall survival vs. 20 %; p = 0.001) and in patients with fewer than 10 % vital tumour cells as compared to those with >10 % (65 % 5-year overall survival vs. 18 %; p < 0.001). A low mitotic count was associated with a longer disease-free survival (p = 0.02). Complete pathological response and the presence of fewer than 10 % vital tumour cells after pre-operative CRT are both associated with a more favourable prognosis. A modification of the pathological staging system after radiotherapy, incorporating the percentage of vital tumour cells, is proposed.