Objective: People with severe mental illness are much more likely to smoke than are members of the general population. Smoking cessation interventions that combine counseling and medication have been shown to be moderately effective, but quit rates remain low and little is known about the experiences of people with severe mental illness in smoking cessation interventions. To address this gap in knowledge, we conducted a qualitative study to investigate factors that help or hinder the smoking cessation efforts of people with severe mental illness. Methods: We recruited 16 people with severe mental illness who had participated in a clinical trial of two different smoking cessation interventions, one involving nicotine replacement therapy only and the other nicotine replacement therapy combined with motivational interviewing and a peer support group. We conducted open-ended, semi-structured interviews with participants, who ranged in age from 20 to 56 years old, were equally distributed by gender (eight men and eight women), and were predominantly Caucasian (n = 13, 81%). Primary mental illness diagnoses included schizophrenia/schizoaffective disorder (n = 6, 38%), depression (n = 5, 31%), bipolar disorder (n = 4, 25%), and anxiety disorder (n = 1, 6%). At entry into the clinical trial, participants smoked an average of 22.6 cigarettes per day (SD = 13.0). Results: Results indicated that people with mental illness have a diverse range of experiences in the same smoking cessation intervention. Smoking cessation experiences were influenced by factors related to the intervention itself (such as presence of smoking cessation aids, group supports, and emphasis on individual choice and needs), as well as individual factors (such as mental health, physical health, and substance use), and social-environmental factors (such as difficult life events and social relationships). Conclusions: An improved understanding of the smoking cessation experiences of people with severe mental illness can inform the delivery of future smoking cessation interventions for this population. The results of this study suggest the importance of smoking cessation interventions that offer a variety of treatment options, incorporating choice and flexibility, so as to be responsive to the evolving needs and preferences of individual clients.