Cross-sectional findings have shed considerable light on the relationships between illness stigma and psychological outcomes among persons living with HIV/AIDS in the United States. However, no studies have examined the possible long-term consequences of illness stigma on mental health among Asians and Pacific Islanders living with HIV/AIDS, a group particularly vulnerable to HIV stigma due to ingrained sociocultural norms. This 2-year longitudinal study examined the relationship between five HIV-stigma factors (social rejection, negative self-worth, perceived interpersonal insecurity, financial insecurity, discretionary disclosure) and changes in psychological distress dimensions (self-esteem, hopelessness, dread, confused thinking, sadness, anxiety) among a convenience sample of 44 HIV-seropositive Asians and Pacific Islanders in New York City from 2002 to 2004. Undocumented Asians independently endorsed higher levels of perceived interpersonal insecurity and lower levels of self-esteem than documented participants at both baseline and 2-year follow-up. Results from hierarchical multiple regression analyses indicated that baseline social rejection and perceived interpersonal insecurity were significantly associated with changes in self-esteem at 2-year follow-up, controlling for baseline self-esteem and physical symptoms at follow-up. An interaction effect between baseline financial insecurity and discretionary disclosure was significantly associated with dread at 2-year follow-up. Findings highlight the importance of stigma reduction interventions that: (1) recognize multiple layers of stigma based sexual orientation, gender, and immigration status; and (2) address both individual and structural constraints that perpetuate HIV-stigma among Asians and Pacific Islanders in the United States.