INTRODUCTION: Primary tumor resection (PTR) in patients with metastatic unresectable colorectal cancer is less and less used to prevent local complications. Although its therapeutic effect is debated, poor data are available about the activity of chemotherapy (CHT) after PTR. The study aims to evaluate trials that compared PTR followed by CHT vs. CHT alone. METHODS: After a literature search on two databases by predefined criteria, studies published from 2011 to 2021 were selected. All studies evaluating the progression-free survival (PFS) of patients receiving CHT after PTR or not were included in a meta-analysis. Finally, 18 possible moderating variables were extracted from each study and examined. RESULTS: Eleven trials reported a reduced risk of progression after first-line CHT among patients receiving PTR (HR 0.72, CI 0.66-0.79). The heterogeneity was moderate (Q = 17.52; p-value = 0.093) and the grade of inconsistence intermediate (I = 37.21%). Among moderating variables, female sex and low percentage of patients with liver metastases were related with a stronger effect size of PTR on PFS, whereas a longer OS and a trend to better PFS was evident after poly-chemotherapy regimens. CONCLUSION: PTR could improve the results of first-line CHT in patients with unresectable colorectal cancer with low tumor burden only in the subgroup receiving more aggressive chemotherapy.