Purpose: To evaluate long-term outcomes and identify prognostic factors for stoma construction following loose seton placement in patients with Crohn disease (CD)-associated perianal fistulas. Methods: This single-center, retrospective study included 136 patients who underwent initial loose seton placement for CD-associated perianal fistulas between 1999 and 2021, with at least 3 years of follow-up. Patient demographics, anorectal findings, and perioperative pharmacotherapy were assessed. Prognosis was defined as the cumulative incidence of stoma formation. Independent risk factors were identified using multivariate logistic regression. The association between postoperative molecular-targeted therapy and stoma-free survival was further analyzed in patients with severe anal ulceration and rectal stricture (high-risk features). Kaplan-Meier curves and log-rank tests were used for comparisons. Results: During follow-up, 42 patients required stoma construction. Severe anal ulceration (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.04–5.38; P=0.039), rectal stricture (OR, 2.84; 95% CI, 1.09–7.37; P=0.032), and absence of postoperative molecular-targeted therapy (OR, 0.36; 95% CI, 0.15–0.84; P=0.018) were independent risk factors. In patients with severe anal ulceration, the cumulative stoma construction rate was significantly lower with postoperative molecular-targeted therapy (P=0.018). No significant difference was observed in patients with rectal strictures (P=0.058). Conclusion Severe anal ulceration, rectal stricture, and absence of postoperative molecular-targeted therapy were independently associated with stoma construction. Postoperative molecular-targeted therapy improved stoma-free survival in patients with severe anal ulceration. Individualized treatment strategies, including early pharmacological intervention, may improve long-term outcomes and preserve anorectal function. Tailoring treatment according to lesion characteristics may reduce stoma formation and enhance quality of life in CD-associated perianal disease.