To examine whether an antegrade or retrograde crossing strategy for treatment of iliac artery chronic total occlusions (CTOs) is associated with differences in procedural or midterm outcomes. A dual-center retrospective cohort study was conducted in 168 patients (mean age 66.4±10.6 years; 116 men) treated for CTOs in 110 common iliac arteries (CIA), 52 external iliac arteries (EIA), and 26 combined CIA/EIAs. Logistic regression models were developed to determine the association between crossing strategy and procedural complications, 1- and 3-year target lesion revascularization (TLR), and major adverse limb events (MALE). Results are presented as the odds ratio (OR) and 95% confidence interval (CI). An initial antegrade strategy was more common for EIA CTOs (p<0.005), and an initial retrograde strategy was more often used in CIA (p<0.005) and combined CIA/EIA (p<0.005) CTOs. Crossover to an alternate approach was required in 27.6% of initial antegrade attempts and 9.6% of initial retrograde attempts. EIA CTOs were the most likely lesions to be treated successfully with the initial attempt (either strategy). In all, 123 (65.4%) lesions were successfully crossed with a final retrograde approach and 65 with a final antegrade approach. Overall target lesion success was high for both groups (95.1% vs 93.2%, p=0.456). Lesions treated with a final retrograde approach were shorter (75.3±34.9 vs 87.6±31.3 mm, p=0.005) and were more likely to be treated with a reentry device (34.2% vs 9.2%, p<0.001) and with balloon-expandable stents (39.2% vs 17.7%, p=0.005). The final antegrade approach was associated with a lower risk of target lesion complications (OR 0.07, 95% CI 0.01 to 0.81, p=0.034). The two crossing approaches were associated with similar estimates of 1- and 3-year TLR and MALE. A final antegrade approach was associated with lower rates for complications but the 2 approaches were similar in terms of lesion success, TLR, and MALE. The EIA CTOs were more likely to be treated with an antegrade approach and more likely to be crossed successfully with the initial approach irrespective of the crossing direction.