Nicotine dependence (ND) and major depression (MD) are highly prevalent disorders that frequently co-occur. Less is known about which aspects of ND are most strongly associated with MD. The present study was designed to determine if subtypes of smokers exist and differ in their risk of MD and lifetime MD symptoms. Latent class analysis was used to identify profiles of DSM-IV ND criteria for 8,842 daily smokers drawn from the larger 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). We found evidence for 4 distinct subtypes of smokers mainly characterized by increasing levels of ND severity, by number of criteria endorsed. We found a dose-response relationship between classes by increasing ND severity and odds of past-year MD and lifetime depression criteria. Class 2 was characterized by higher symptom endorsement probabilities (SEPs) for wider range of ND criteria and a higher odds of MD (OR=3.66) compared to class 3, which was characterized by higher SEPs for physiological ND criteria, higher prevalence of ND (class 2, 71.50% vs. class 3, 81.57%), and a lower odds of MD (OR=2.15). A post hoc contrast showed these two distinct classes of respondents with mild to moderate ND significantly differed in their likelihood of MD comorbidity (F=12.25, 1 df, p=0.0008). ND severity mainly characterized the classes, but unique differences may exist between smokers with mild to moderate ND. Individuals with symptom profiles not characterized by physiological dependence endorse wider range of ND criteria and have a higher likelihood of MD.