Simple SummaryColorectal cancer (CRC) is mainly treated by surgical resection. However, surgery induces a state of immunosuppression and leads to attenuation of the cellular immunity that is so vital for successful defense against infections and malignant cells. Because this immunosuppression depends on the extent of the surgical trauma, it is hypothesized that minimally invasive surgical approaches such as laparoscopy have beneficial effects for cellular immunity, leading to fewer infectious complications as well as lower rates of locoregional recurrence and distant metastasis. Better short- and long-term oncologic outcomes are reported by clinical trials, and immunologic mechanisms might substantially contribute to these observations. Herein, the authors systematically compare minimally invasive laparoscopic surgery with open surgery in terms of their respective influences on certain aspects of cellular immunity.AbstractColorectal cancer (CRC) is the third most common cancer worldwide. The main treatment options are laparoscopic (LS) and open surgery (OS), which might differ in their impact on the cellular immunity so indispensable for anti-infectious and antitumor defense. MEDLINE, Embase, Web of Science (SCI-EXPANDED), the Cochrane Library, Google Scholar, ClinicalTrials.gov, and ICTRP (WHO) were systematically searched for randomized controlled trials (RCTs) comparing cellular immunity in CRC patients of any stage between minimally invasive and open surgical resections. A random effects-weighted inverse variance meta-analysis was performed for cell counts of natural killer (NK) cells, white blood cells (WBCs), lymphocytes, CD4+ T cells, and the CD4+/CD8+ ratio. The RoB2 tool was used to assess the risk of bias. The meta-analysis was prospectively registered in PROSPERO (CRD42021264324). A total of 14 trials including 974 participants were assessed. The LS groups showed more favorable outcomes in eight trials, with lower inflammation and less immunosuppression as indicated by higher innate and adaptive cell counts, higher NK cell activity, and higher HLA-DR expression rates compared to OS, with only one study reporting lower WBCs after OS. The meta-analysis yielded significantly higher NK cell counts at postoperative day (POD)4 (weighted mean difference (WMD) 30.80 cells/µL [19.68; 41.92],p <0.00001) and POD6–8 (WMD 45.08 cells/µL [35.95; 54.21],p <0.00001). Although further research is required, LS is possibly associated with less suppression of cellular immunity and lower inflammation, indicating better preservation of cellular immunity.