Background: The interaction of genetics with environmental factors can influence asthma development. ORMDL3 and Scca1 are known asthma risk genes, while cigarette smoke (CS) exposure in early life is an established risk factor for wheezing and asthma. Thus, we asked how CS affects the fitness and morphology of airways of D. melanogaster larvae after overexpression (OE) or knock-down (KD) of the fly homologs dORMDL and Spn43Aa. Methods: Fly lines with KD or OE of Spn43Aa and dORMDL in the airways were created using the Gal4-UAS system. Larvae were exposed to CS, receiving 3 puffs/min for one hour on 3 consecutive days. Survival of adult flies was monitored until natural death. The structure of airways was analyzed with microscopy, including measuring the length and number of branches of terminal cells, as well as their total number. Results: The lifespan of adult males was reduced by OE of Scca1 and ORMDL and further decreased by CS. Females with either Scca1 or ORMDL OE had a shorter lifespan only after CS exposure. Scca1 and ORMDL KD did not affect the lifespan. However, male lifespan was shortened after additional CS exposure. Terminal cell length varied between sexes, with a significant difference observed in females with Scca1 OE after CS exposure. Larvae with Scca1 OE had higher numbers of terminal cells, which was increased by CS. Conclusion: We propose that Scca1 and ORMDL play a role in regulating the morphology of airways, while fitness depends on both CS exposure and genetic factors. We will now investigate the epithelial cell proliferation and cell integrity of the airways.