Background: This study examines how shield-triggered autoinjectors (AIs), for subcutaneous drug delivery, affect injection depth. It focuses on shield size and applied force, parameters that could potentially lead to inadvertent intramuscular (IM) injections due to tissue compression. Method: A blinded ex-vivo study was performed to assess the impact of shield size and applied force on injection depth. Shields of 15, 20, and 30 mm diameters and forces from 2 to 10 N were investigated. The study involved 55 injections in three Landrace, Yorkshire, and Duroc (LYD) pigs, with injection depths measured with computed tomography (CT). An in-vivo study, involving 20 injections in three LYD pigs, controlled the findings, using fluoroscopy (FS) videos for depth measurement. Results: The CT study revealed that smaller shield sizes significantly increased injection depth. With a 15 mm diameter shield, 10 N applied force, and 5 mm needle protrusion, the injection depth exceeded the needle length by over 3 mm. Injection depth increased with higher applied forces until a plateau was reached around 8 N. Both applied force and size were significant factors for injection depth (analysis of variance [ANOVA], P <.05) in the CT study. The FS study confirmed the ex-vivo findings in an in-vivo setting. Conclusions: The study demonstrates that shield size has a greater impact on injection depth than the applied force. While conducted in porcine tissue, the study provides useful insights into the relative effects of shield size and applied force. Further investigations in humans are needed to confirm the predicted injection depths for AIs.