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Poor mental health among human immunodeficiency virus (HIV)-positive people who inject drugs (PWID) may contribute to stigma, and together they act as barriers to medical care. This analysis aims to examine factors associated with the mental health of PWID and their network contacts, and the association of poor mental health with the experience of HIV-related stigmatizing events, with HIV-related social support, and with perceived access to care. Data were collected during the Transmission Reduction Intervention Project (TRIP) conducted in Athens, Greece (2013–2015). PWID (n = 292; n = 122 HIV-positive) were interviewed both at baseline and follow-up. Items of depression, anxiety, and general positive affect subscales of the Mental Health Inventory were used to explore the psychological distress and well-being of participants at follow-up. Items of the Access to Care Scale were used to evaluate perceived access to medical care at baseline and follow-up. Linear regression showed that unemployment was positively related to depression (β = 1.49, p = 0.019), while injecting drug use was a risk factor for a low general positive affect score (β = −3.21, p = 0.015). Poor mental health was not linked to HIV-related stigma or social support. Positive perception of access to care was associated in multivariable analyses with low depression (β = −0.22, p = 0.049). The perceived access to care score improved from baseline to follow-up (p = 0.019) and HIV-positive participants had a higher score than HIV-negative participants. Future interventions should include targets to improve the mental well-being of participants, reduce psychosocial distress, and minimize perceived barriers to accessing medical care. [ABSTRACT FROM AUTHOR]