Type III collagen plays an important role in activating platelets, forming thrombus, and maintaining the mechanical properties of arteries. This study aimed to test the hypothesis that genetic variants of COL3A1 (gene encoding type III collagen) contribute to recurrence and prognosis of stroke. We investigated the associations of three variants (rs2138533, rs11887092, and rs1800255) in the COL3A1 gene with stroke recurrence and prognosis in 1,544 patients with three subtypes of stroke: lacunar infarction (n = 442), atherothrombotic infarction (n = 670), and hemorrhage (n = 432). These associations were evaluated by Kaplan-Meier analysis and Cox regression models. Patients were followed up for 4.5years. The A allele of rs1800255 in the COL3A1 gene coding region was significantly associated with a reduced risk of stroke recurrence in patients with lacunar infarction (adjusted hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.36-0.93, P = 0.024), but there was an increased risk of all-cause mortality of atherothrombotic patients (adjusted HR 1.43, 95% CI 1.01-2.00, P = 0.044). The TT genotype of rs2138533 showed a significantly increased risk of death caused by cardiovascular disease or stroke in lacunar infarct patients (adjusted HR 2.98, 95% CI 1.27-6.98, P = 0.012), but there was a reduced risk of all-cause mortality for patients with intracerebral hemorrhage (adjusted HR 0.34, 95% CI 0.12-0.93, P = 0.036). The G allele of rs11887092 increased the risk of stroke recurrence in patients with atherothrombotic stroke (adjusted HR 1.59, 95% CI 1.04-2.44, P = 0.035). In conclusion, variants of COL3A1 might play a vital role in determining the risk of recurrence and prognosis after stroke.