Down-regulation of CDK5RAP3 in gastric cancer was correlated with poor prognosis. CDK5RAP3 suppressed gastric cancer tumorigenesis via β-catenin inhibition. CDK5RAP3 inhibited β-catenin via GSK-3β phosphorylation suppression. The prognostic value of CDK5RAP3 in gastric cancer depends on β-catenin status.