Abstract Background: Colorectal cancer (CRC) is the third most common cancer in men and women worldwide. Although improved screening has significantly reduced its incidence, the occurrence and death rates of CRC in younger people have increased in the last few decades. Following initial successes in melanoma treatment, immunotherapy has rapidly become a major treatment modality for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) CRCs. Previous reports have demonstrated the association of apolipoprotein C1 (APOC1) with several cancers; however, the function of APOC1 in MSI-H CRC remains unknown. Therefore, this study aimed to investigate the role of APOC1 in clinical prognosis and immunotherapy drug responses in CRC.Results: The Cancer Genome Atlas (TCGA) database was searched, and through relevant machine learning algorithms and bioinformatics correlation analysis, APOC1 was identified as a gene possibly associated with CRC. The correlation between APOC1 expression, clinical prognosis, and response to immunotherapeutic drugs was also analysed based on public data. The findings were then validated using independent datasets from different technology platforms, including single-cell datasets. MSI-H CRC transcriptome data were downloaded from TCGA, and the tumour microenvironment (TME) model classified the TME of MSI-H CRC patients into four clusters; the IE (immune-enriched, non-fibrotic) subtype and other subtypes had less overlap and were relatively discrete. The screened differentially expressed genes (DEGs) were overlapped, and one common DEG (APOC1) was screened out. The results showed that APOC1 expression in CRC was positively correlated with tumour mutation burden, MSI, neoantigen, and signalling pathways such as myeloid cells and cytokines and immune scores. However, APOC1 expression in CRC was significantly negatively correlated with MMR-related genes. APOC1 was highly correlated with immune-related cell enrichment and immune checkpoints in colon adenocarcinoma patients and was more highly expressed in malignant cells than in normal cells, according to the single-cell data analysis. APOC1 expression in tumour tissues was significantly higher than that in normal tissues. The same conclusions can be obtained from different detection techniques and platforms. Conclusions: It was revealed that the APOC1 tumour level in MSI-H CRC was correlated with clinical prognosis and response to immunotherapeutic drugs.