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Closed-circuit rebreather (CCR) and helium-based breathing mixtures are widely used in technical diving. This study compared the effects of Heliox and Trimix on pulmonary function and decompression stress during CCR dives. Nineteen divers performed a standardized dive (50 ± 3 msw, 147 ± 10 min) using Heliox (16% O₂/84% He; n = 9) or Trimix (16% O₂/32% He/52% N₂; n = 10). Pre- and post-dive venous gas emboli (VGE), pulmonary function, lung ultrasound, heart rate variability, and inflammatory parameters were assessed. VGE were detected in all Heliox divers but in only 50% of Trimix divers. Heliox exhibited higher VGE counts 45 min post-dive than Trimix (12 [IQR 3-32] vs. 0 [IQR 0-6], p = 0.03); this difference disappeared by 90 min. No clinically significant pulmonary function changes were observed. Lung diffusion capacity decreased moderately regardless of breathing gas (-6% ± 7%). Lung ultrasound revealed minor transient B-line changes. Dive induced mild inflammatory responses, including neutrophilia and increased MRP8/14 in both groups. Heliox divers also showed transient complement activation alongside increased circulating platelets. CCR dives induced limited pulmonary stress, without gas-dependent differences. Although Heliox may promote a higher post-dive VGE burden and inflammatory responses, the relationship between these physiological effects and decompression sickness risk remains uncertain.