Background <p>Fistulizing Crohn’s disease (CD) is a severe phenotype associated with morbidity and impaired health-related quality of life (HRQoL). However, it remains unclear whether HRQoL impairment is driven by fistula presence or ongoing inflammatory activity. This study aimed to evaluate the association of fistulizing disease, disease activity, and treatment exposure with HRQoL.</p> Methods <p>This cross-sectional study included consecutive adult patients with CD attending a tertiary inflammatory bowel disease clinic. Patients were classified as having fistulizing or non-fistulizing disease. The primary outcome was HRQoL, assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ) and its four subdomains. Luminal and perianal disease activities were evaluated using the Crohn’s Disease Activity Index (CDAI) and Perianal Disease Activity Index (PDAI). Associations were analyzed using t-test or Mann–Whitney U test, Chi-square or Fisher’s exact test, and Spearman’s rank correlation, as appropriate.</p> Results <p>A total of 209 patients were included (mean age 38.6 ± 13.1&#xa0;years; 36.8% female); 106 (50.7%) had fistulizing disease, predominantly perianal. Female sex was associated with lower total IBDQ scores (<i>p</i> &lt; 0.001). CDAI showed a moderate inverse correlation with total IBDQ score (<i>ρ</i> = −0.538, <i>p</i> &lt; 0.001), and PDAI was also negatively correlated with total IBDQ score (<i>ρ</i> = −0.372, <i>p</i> = 0.001). Similar correlations were observed across all IBDQ subdomains. Fistula presence, including perianal fistulas, smoking status, prior surgery, and biologic exposure were not significantly associated with HRQoL.</p> Conclusions <p>Active luminal and perianal inflammation, rather than fistula presence alone, appears to be the principal determinant of HRQoL in CD.</p>