Background: Intramuscular (IM) injections are often used to give medications like atropine, pralidoxime, epinephrine, naloxone, antibiotics, and vaccines. The efficacy of these medications relies on successful delivery into the muscle beneath the skin and subcutaneous tissues. The skin to muscle depth (STMD) varies with sex, age, body fat percentage, and injection site. The existing literature indicates substantial differences in STMD between males and females, with females frequently being at greater risk of unintentional subcutaneous administration. Unintended subcutaneous administration may cause slower absorption and failure to obtain therapeutic concentrations of the medication. This issue has implications in military healthcare, particularly in far-forward settings where auto-injectors are used for life-saving medications. Despite significant research, STMD has not been evaluated in an active-duty military population, where IM injections are important in Tactical Combat Casualty Care (TCCC) guidelines. Given the importance of manual IM injections and auto-injectors in combat settings, disparities in STMD could impact medication effectiveness and survival rates. This study aims to compare STMD in active-duty male and female service members to determine if a sex-based disparity exists, potentially guiding improvements in military medical care. Methods: This is a cross-sectional study comparing STMD in active-duty males and females using ultrasound at four common sites for intramuscular injection: deltoid, dorsogluteal, ventrogluteal, and vastus lateralis. Participants will be recruited from the Madigan general surgery clinic and preoperative holding area. Measurements will be repeated twice bilaterally in a relaxed state and when pressure is applied using the ultrasound probe to simulate the use of an autoinjector. Body mass index (BMI), age, military occupational specialty (MOS) activity level, and body fat percentage will be collected to assess other variables that may help predict adequate needle length for intramuscular injection. Data will be analyzed to determine if there is a significant difference in STMD in males and females. Results: A total of 101 active-duty participants (51 males, 50 females) were enrolled. Females had significantly greater skin-to-muscle depth (STMD) than males at the vastus lateralis, ventrogluteal, and dorsogluteal sites (p<0.05), with no difference at the deltoid. Across BMI, age, and body fat percentage classifications, females consistently demonstrated greater STMD, with the largest difference at vastus lateralis relaxed in the 42–46 age group (24.2 mm, p<0.0001). STMD increased with BMI in both sexes but rose faster in females. Risk of subcutaneous injection (SQI) was higher in females (40%) compared to males (8%), most often at the dorsogluteal relaxed site. At the vastus lateralis, 12% of females and no males were at risk for SQI given standard needle lengths (18–23 mm). Conclusion: Females demonstrated greater skin-to-muscle depth (STMD) than males across most injection sites, most notably at the vastus lateralis. STMD increased with BMI and body fat percentage, with a steeper rise in females. Standard auto-injector needle lengths (18–23 mm) may be insufficient for many females, particularly those with higher BMI or in older age groups. These findings highlight the need for personalized, sex-specific auto-injector design and deployment strategies to ensure reliable intramuscular delivery. Addressing this gap could improve medication efficacy and reduce mortality, especially in military and far-forward care environments.