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This study aims to describe the association of first trimester co-use of tobacco and cannabis with maternal immune response and psychosocial well-being, relative to tobacco use only. A preliminary midpoint analysis included 138 pregnant women with biologically verified tobacco use, 38 of whom (28%) also tested positive for recent cannabis use. Maternal perceived stress (Perceived Stress Scale), depressive symptoms (Edinburgh Postnatal Depression Scale), and serum immune markers (IL-1β, IL-2, IL-6, IL-8, IL-10, TNFα, CRP, MMP8), were collected, although cytokine data were only available for 122 women. Participant average age was 29.1 years, approximately half had a high school education or less, and half were unemployed. Compared to tobacco only users, co-users were more likely to be non-White, younger and more economically disadvantaged. In the adjusted linear regression models, TNF-α levels were significantly lower among co-users relative to tobacco only users, after adjusting for age, race/ethnicity, body mass index and tobacco use group (tobacco cigarettes, electronic nicotine delivery devices [ENDS] or both). TNF-α was the only immune marker found to be significant in this analysis. Measured stress levels (M = 5.9, SD = 3.3; potential range 0–16) and depression scores (M = 7.8, SD = 5.8; potential range 0–30) were low across all participants and did not differ as a function of co-use. Preliminary results suggest women co-using during the first trimester exhibit decreased pro-inflammatory immune responsivity on one out of eight markers. Further research is needed to determine the impact of this immune modulation on fetal health outcomes and the unique contribution of cannabis. • Describing the association of first trimester co-use of tobacco and cannabis with inflammation and psychosocial well-being. • The parent study of this preliminary analysis aims to determine the impact of tobacco use on inflammation and birth outcomes. • Pregnant women who reported co-use were younger and less likely to be white, compared to tobacco only users. • Thirty percent of participants were positive for recent use of an illicit substance other than cannabis in first trimester. • First trimester co-use of tobacco and cannabis decreased pro-inflammatory immune response, specifically reduced TNF-α levels. [ABSTRACT FROM AUTHOR]