Background: A promising treatment option for adolescents with treatment-resistant depression is high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex (L-DLPFC). Conventional coil placement strategies for rTMS in adults include the 5-cm rule, the Beam F3 method, and the magnetic resonance imaging (MRI) neuronavigation method. The purpose of this study was to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents. Methods: Ten consenting and assenting depressed adolescents (4 females, age: 15.9 +/- 1.1) participated in an open-label rTMS treatment study. Participants were offered MRI-guided rTMS 5 times per week over 6 to 8 weeks. To compute the induced E-field, a head model was generated based on MRI images, and a figure-8 TMS coil (Neuronetics) was placed over the L-DLPFC using the four targeting approaches. Results: Results show that there was a significant difference in the induced E-field at the L-DLPFC between the four targeting methods (chi-squared = 24.7, p < 0.001). Post hoc pairwise comparisons show that there was a significant difference between any two of the targeting methods (Holm adjusted p < 0.05), with the 5-cm rule producing the weakest E-field (46.0 +/- 17.4 V/m), followed by the F3 method (87.4 +/- 35.4 V/m), followed by the MRI-guided (112.1 +/-14.6 V/m), and followed by the computationally optimized method (130.1 +/- 18.1 V/m). The Bartlett test of homogeneity of variances show that there was a significant difference in sample variance between the groups (K^2 = 8.0, p < 0.05), with F3 having the largest variance. In participants who completed the full course of treatment, the median E-field strength in the L-DLPFC was correlated with the change in depression severity (r = -0.77, p < 0.05). Conclusions: The E-field models revealed inadequacies of scalp-based targeting methods compared to MRI-guidance. Computational optimization may further enhance E-field dose delivery to the treatment target.