Rationale: Numerous studies have demonstrated that e-cigarettes can impact respiratory immune homeostasis; however, the extent of these effects remains an active area of investigation, and most previous studies were conducted with model systems or subjects exposed to 3rd generation e-cigs, such as vape pens and box mods. Objective: Given the rise in popularity of nicotine-salt-containing pod and disposable e-cigarettes (4th generation), we set out to better understand the respiratory effects of these newer e-cigarettes and to compare their effects to early generation devices. Methods and Measurements: We collected induced sputum samples from a cohort of non-smokers, smokers, 3rd generation e-cigarette users, and 4th generation e-cigarette users (n = 20-30 per group) and evaluated the cellular and fluid phase composition for markers of inflammation, host defense, and lung injury. Main Results: 4th generation e-cigarette users had significantly more bronchial epithelial cells in sputum, suggestive of airway injury. Levels of sICAM1 and sVCAM1 were significantly lower in 4th generation e-cigarette users in comparison with all other groups, and CRP, IFN-, MCP-1, uteroglobin, and VEGF were significantly lower in 4th vs 3rd generation e-cigarette users, suggestive of overall immune suppression in 4th generation e-cigarette users. Predictive modeling also demonstrated clear separation between exposure groups, indicating that the overall mediator milieu is different between groups, particularly 4th generation e-cigarette users. Conclusions: Our results indicate disrupted immune homeostasis in 4th generation e-cigarette users and demonstrate that the biological effects of 4th generation e-cigarette use are unique compared to those associated with previous generation e-cigarettes.