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Smartphone overuse can harm individual health and well-being. Although several studies have explored the relationship between problematic or excessive smartphone use and mental health, much less is known about effects on self-esteem, which is essential in having a healthy life, among adults with mental health disorders, including internet gaming disorder. Furthermore, given that smartphone usage differs by gender, little is known about gender differences in the relationship between smartphone overuse and self-esteem. The objective of this study was to assess self-esteem among individuals with mental health disorders and explore the relationship with excessive smartphone use. Participants were selected based on their responses to the internet gaming disorder assessment, which includes 9 items developed based on Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, from among a Korean cohort of smartphone users aged 20-40 years, resulting in a sample of 189 participants (men:120, women: 69). The Rosenberg self-esteem scale and the Korean smartphone addiction proneness scale were utilized to assess the outcome self-esteem with excessive smartphone use as the primary independent variable. Guided by the Bowlby attachment theory and prior studies, we selected several covariates. Generalized linear regression analyses, as well as subgroup analyses by gender, were performed. Among adults with internet gaming disorder, the average Korean smartphone addiction proneness scale score was significantly higher in women than that in men (41.30 vs. 37.94; P=.001), and excessive smartphone use was significantly more prevalent in women than it was in men (30.43% vs. 20.83%; P=.02). Our findings from the generalized linear regression analyses indicated that an increase in Korean smartphone addiction proneness scale score had a negative relationship with self-esteem among those with internet gaming disorder (β=–0.18, P=.001). Furthermore, our interaction models showed that, among those with internet gaming disorder, more men than women had lower self-esteem associated with an increase in Korean smartphone addiction proneness scale score and a high degree of smartphone overuse (β=–0.19, P=.004; β=–3.73, P<.001). Excessive smartphone use was found to be adversely associated with self-esteem among young and middle-aged adults with internet gaming disorder; notably, more men than women were negatively influenced (regarding self-esteem) by smartphone overuse. Based on our findings, more efforts should be made to reduce excessive or problematic smartphone use by considering developing public health interventions or policy, particularly among those with mental health disorders such as internet gaming disorder.