Background & Objective: A growing awareness exists that the tumour microenvironment (TME) contributes to cancer progression. Reporting infiltrating immune cells and tumour buds (TBs) within the TME, has been shown to correlate with clinical outcome. Traditionally these are studied in isolation of each other. The aim of this study is to evaluate the prognostic significance of their association and interaction in patients with stage II colorectal cancer disease (CRC). Method: Multiplexed immunofluorescence and automated image analysiswere used for the quantification of CD3+, CD8+ lymphocytes; CD68+ , CD163+ macrophages and TBs, across whole slide images (n=114). Machine learning algorithms were used for feature selection and prognostic risk model development. Results: A higher number of TBs was correlated with advanced pTstage (P = 0.004). A higher number of CD3+ cells at the invasive margin was correlated with a lower number of TBs (P = 0.03). A higher ratio of CD68+/CD163+ cells at the tumour core was associated with a higher number of TBs (P < 0.0001). A novel prognostic signature, derived from integrating TBs, lymphocytes and their spatial relationship reported a cohort stratification (P < 0.0001) which outperformed the clinical gold standard of pT stage (P = 0.003). Conclusion: This study provides evidence that the interaction between lymphocytes and TBs holds prognostic significance in stage II CRC and the combination of these features shows a prognostic significance, which exceeds that of each in isolation.