Introduction: Noninvasive neuromodulation (NM) via transcranial magnetic stimulation (TMS) is increasingly applied to treat neurological and psychiatric disorders. However, NM effects are highly variable between subjects. E-field orientation (EFO) during NM protocols may heavily contribute to this variability. Investigating the influence of EFO during NM could lead to improved therapeutic protocols by enabling more tailored approaches for patient-specific NM. In the present study, we aimed to examine the influence of varying EFO during continuous theta burst stimulation (cTBS) on the modulation of motor-evoked potentials (MEPs). Methods: 20 healthy volunteers (8 F; mean age 25.7±2.7 years) took part in this prospective, single blind sham-controlled crossover study consisting of three neuronavigated TMS sessions. The sessions differed only in EFO during cTBS (parallel to optimal EFO for MEP generation [OPT], 90° rotated from OPT [90], 45° rotated from OPT with 7.3 cm spacer [SHAM]). Electromyography was recorded from abductor pollicis brevis, first dorsal interosseous, and adductor digiti minimi muscles during stimulation of the abductor pollicis brevis (APB) motor hotspot. 4 blocks (PRE, POST1, POST2, POST3) with 30 MEPs each were elicited from the motor hotspot. Between the PRE and POST1 block, 40 s of cTBS were performed using one of the three EFO paradigms. Individual POST blocks were separated by a 2 min interval. MEPs were analyzed with linear mixed effects modeling augmented by bootstrapping. Results: A total of 19,830 MEPs were analyzed. Progression through the trial blocks led to heightened MEP amplitudes (e.g., POST3 vs. PRE; log-estimate 0.244, t = 21.43), and later trials were significantly associated with higher MEP amplitudes (spearman′s rho 0.981; p < 0.001). Additionally, on the group level, a significant albeit slight influence of EFO on MEP amplitudes with the 90 paradigm leading to facilitation, and SHAM paradigm leading to suppression of MEP amplitudes was observed when compared to the OPT paradigm (log-estimate 90: 0.135, t = 13.604; log-estimate SHAM: -0.043, t = -4.283). On the subject level, we observed strong heterogeneity between individuals regarding their response to cTBS using varying EFO. Discussion: We observed that MEP amplitudes following cTBS differed significantly based on EFO during NM. This implies that for a given desired NM result, individual EFO optimization may act as an avenue to maximize the NM effect. Therapeutic NM applications might consider EFO as a parameter of interest to be investigated in clinical studies. Additionally, prolonged single-pulse stimulation appeared to possess a NM quality of its own, which should be considered in TMS studies employing single-pulse protocols.