Background Optimal duration of antimicrobial therapy (AT) for catheter-related septic deep venous thrombosis (DVT) is unknown. We aimed to compare the outcomes of patients receiving short-course AT (≤21 days) versus prolonged-course AT (>21 days). Methods This was a monocentric retrospective study comparing adults with catheter-related septic DVT from 2015 to 2020 treated with short- or prolonged-course AT. A propensity score–weighted analysis was used to mitigate potential bias. The primary outcome was a composite of all-cause mortality or recurrent bloodstream infection 30 days after AT discontinuation. Results Of 172 patients with catheter-related septic DVT, 104 were treated with prolonged-course AT and 68 with short-course AT. In the propensity score analysis, we found no significant difference in 30-day all-cause mortality or relapse between the 2 groups (inverse probability of treatment weighted hazard ratio [wHR], 2.16 [95% confidence interval {CI},.68–6.88]; P =.192). No differences in 90-day all-cause mortality and 90-day relapse were observed between the treatment groups (wHR, 1.01 [95% CI,.49–2.05], P =.987 and 1.13 [95% CI,.08–15.62], P =.928, respectively). Conclusions A 21-day AT could be an effective and safe option to treat catheter-related septic DVT. Further randomized studies are needed to establish the optimal duration of AT for patients with catheter-related septic DVT. [ABSTRACT FROM AUTHOR]