Aim: We explored how acculturation and self-actualization affect depression in the HIV-positive Asians and Pacific Islanders immigrant population. Background: Asians and Pacific Islanders are among the fastest growing minority groups in the USA. Asians and Pacific Islanders are the only racial/ethnic group to show a significant increase in HIV diagnosis rate. Design: A mixed-methods study was conducted. Methods: Thirty in-depth interviews were conducted with HIV-positive Asians and Pacific Islanders in San Francisco and New York. Additionally, cross-sectional audio computer-assisted self-interviews were conducted with a sample of 50 HIV-positive Asians and Pacific Islanders. Content analysis was used to analyse the in-depth interviews. Also, descriptive, bivariate statistics and multivariable regression analysis was used to estimate the associations among depression, acculturation and self-actualization. The study took place from January-June 2013. Discussion: Major themes were extracted from the interview data, including self-actualization, acculturation and depression. The participants were then divided into three acculturation levels correlating to their varying levels of self-actualization. For those with low acculturation, there was a large discrepancy in the Center for Epidemiologic Studies Depression Scale scores between those who had totally lost their self-actualization and those who believed they could still achieve their 'American dreams'. Among those who were less acculturated, there was a significant difference in depression scores between those who felt they had totally lost their ability to self-actualize and those who still believed they could 'make their dreams come true.' Conclusion: Acculturation levels influence depression and self-actualization in the HIV-positive Asians and Pacific Islanders population. Lower acculturated Asian Americans achieved a lower degree of self-actualization and suffered from depression. Future interventions should focus on enhancing acculturation and reducing depression to achieve self-actualization.