Implications of plasminogen activator inhibitor-1 (PAI-1) in colonic polyps remain elusive. A prospective study was conducted with 188 consecutive subjects who underwent colonoscopy at a tertiary referral center. Biochemical parameters, serum PAI-1 levels, PAI-1 single-nucleotide polymorphisms (rs-1799889), and colonic polyp profiles were analyzed at baseline and 24 and 48 weeks postpolypectomy. Of 188 patients (mean age: 56.8 years), 78.7% had adenomas; the median polyp number and size were 2 and 1.2cm, respectively. Multivariate analyses revealed the following baseline associations: PAI-1 levels (95% confidence interval [CI] for estimated β: 0.012–0.223) and polyp pathology (0.294–0.63) with polyp size; polyp size (0.085–0.498) and platelet count (0.013–0.027) with PAI-1 levels. At 24 weeks postpolypectomy, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and platelet count were independently associated with PAI-1 levels. Among patients with colonic adenomas, baseline PAI-1 levels (95% CI odds ratio: 1.06–1.686; cut-off value: >10.65 ng/mL, area under curve: 0.662, P = 0.032) and the PAI-1-rs-17998894G/4G genotype (0.036–0.912) were associated with high-grade dysplasia. Compared with baseline levels, repeated measures analysis of variance showed that PAI-1 levels increased, with concurrent increased HOMA-IR indexes, but decreased alanine transaminase levels and polyp size in follow-up colonoscopies at 24 weeks postpolypectomy. PAI-1 returned to baseline levels, and HOMA-IRs and triglyceride/high-density lipoprotein-cholesterol ratios decreased at 48 weeks postpolypectomy. Taken together, serum PAI-1 levels were positively associated with colonic polyp size and high-grade dysplasia, which was modulated by the PAI-1-rs-17998894G/4G genotype. The beneficial postpolypectomy inflammatory and metabolic alterations might be transiently counter regulated by elevated PAI-1 levels, with a link to HOMA-IR.