Abstract Objective This study was undertaken to investigate the regional burden of enlarged perivascular spaces (EPVSs) in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS) and explore its prognostic relevance. Methods In this retrospective observational study, EPVSs in the temporal lobe (T‐EPVS), centrum semiovale (CS‐EPVS), basal ganglia (BG‐EPVS), midbrain, and hippocampus were visually rated in 68 treatment‐naïve patients with TLE‐HS. Regional EPVS burden was dichotomized into high and low degrees (cutoff: >10 for BG‐EPVS/T‐EPVS; >20 for CS‐EPVS). Cox proportional hazards models were used to determine the potential predictors of seizure freedom (SF; no seizure for >1 year) and delayed SF (SF achieved >6 months after initiating antiseizure medication [ASM]). Multivariate logistic regression using stepwise variable selection based on the Akaike information criterion was performed to investigate whether EPVS burden was associated with medical refractoriness (never achieving SF). Results Of the 68 patients, 20 were classified into the refractory group (29.4%). The high T‐EPVS group had an older epilepsy onset (37.3 ± 12.3 vs. 26.5 ± 13.0 years, p = .005), higher pretreatment seizure density (median = 12.0, interquartile range [IQR] = 5.0–20.0 vs. 4.0, IQR = 2.0–10.5, p = .008), and lower focal to bilateral tonic–clonic seizure prevalence (13.3% vs. 73.6%, p < .001) than the low T‐EPVS group. High T‐EPVS burden (odds ratio [OR] = 10.908, 95% confidence interval [CI] = 1.895–62.789) was an independent predictor of medial refractoriness, along with female sex (OR = 12.906, 95% CI = 2.214–75.220) and ASM treatment duration (OR = .985, 95% CI = .971–.999). The low T‐EPVS group had higher probability of achieving delayed SF than the high T‐EPVS group ( p Log‐rank = .030, p Cox regression = .038), whereas the probability of achieving SF was comparable between the two groups ( p Log‐rank = .053, p Cox regression = .146). Significance Increased T‐EPVS burden may serve as an imaging marker of unfavorable prognosis in patients with TLE‐HS, underscoring the potential role of perivascular dysfunction in diminished ASM response.