As the use and influence of social networking continues to grow, researchers have begun to explore its consequences for psychological well-being. Some research suggests that Facebook use can have negative consequences for well-being. Instagram, a photo-sharing social network created in 2010, has particular characteristics that may make users susceptible to negative consequences. This study tested a theoretically grounded moderated meditation model of the association between Instagram use and depressive symptoms through the mechanism of negative social comparison, and moderation by amount of strangers one follows. One hundred and seventeen 18-29 year olds completed online questionnaires containing demographics, frequency of Instagram use, amount of strangers followed on Instagram, the Center for Epidemiological Resources Scale for Depression, and the Social Comparison Rating Scale. Instagram use was marginally positively associated with depressive symptoms, and positive social comparison was significantly negatively associated with depressive symptoms. Amount of strangers followed moderated the associations of Instagram use with social comparison (significantly) and depressive symptoms (marginally), and further significantly moderated the indirect association of Instagram use with depressive symptoms through social comparison. Findings generally suggest that more frequent Instagram use has negative associations for people who follow more strangers, but positive associations for people who follow fewer strangers, with social comparison and depressive symptoms. Implications of negative associations of social networking for people who follow strangers and the need for more research on Instagram use given its increasing popularity are explored.