INTRODUCTIONMulti-morbidity is a public health priority as it is associated with an increased risk of mortality and a substantial healthcare burden. Smoking is considered a predisposing factor for multi-morbidity, but evidence for an association between multi-morbidity and nicotine dependence is insufficient. This study aimed to explore the association between smoking status, nicotine dependence, and multi-morbidity in China.METHODSWe recruited 11031 Chinese citizens from 31 provinces in 2021 using a multistage stratified cluster sampling strategy to ensure the study population represented national population characteristics. The association between smoking status and multi-morbidity was analyzed using binary logistic regression and multinomial logit regression models. We then analyzed the associations between four kinds of smoking status (age at smoking initiation, cigarette consumption per day, smoking when ill in bed, and inability to control smoking in public places), nicotine dependence, and multi-morbidity among participants who were current smokers.RESULTSCompared with non-smokers, the odds of multi-morbidity were higher among ex-smokers (adjusted odd ratio, AOR=1.40, 95% CI: 1.07–1.85). The risk of multi-morbidity was greater in participants who were underweight/overweight/obese (AOR=1.90; 95% CI: 1.60–2.26) compared with those who were normal weight. and also greater for drinkers (AOR=1.34; 95% CI: 1.09–1.63) than non-drinkers. Compared with children who began smoking at the age of <15 years, participants aged >18 years had a lower likelihood of multi-morbidity (AOR=0.52; 95% CI: 0.32–0.83). People who consumed ≥31 cigarettes per day (AOR=3.77; 95% CI: 1.47–9.68) and those who smoked when ill in bed (AOR=1.70; 95% CI: 1.10–2.64) were more likely to have multi-morbidity.CONCLUSIONSOur findings show that smoking behavior, including initiation age, frequency of daily smoking, and still smoking during illness or in public, is a critical risk factor for multi-morbidity, especially when combined with alcohol consumption, physical inactivity, and abnormal weight (underweight, overweight, or obese). This highlights the crucial effect of smoking cessation in the prevention and control of multi-morbidity, especially in patients with three or more diseases. Implementing smoking and lifestyle interventions to promote health would both benefit adults and prevent the next generation from initiating habits that increase the risk of multi-morbidity.