A complex bidirectional relationship exists between human immunodeficiency virus (HIV) infection and psychotic disorders. The co-occurrence of both conditions is associated with higher morbidity and mortality than their individual occurrence. In this case report, we discuss a 36-year-old people with HIV and first-episode psychotic disorder who benefited from the two-injection start regimen of long-acting aripiprazole without side effects in the context with relevant literature. In people with HIV and psychotic symptoms, a thorough evaluation is required to exclude other known causes of psychosis. With a multidisciplinary approach, proper diagnosis and appropriate treatment can reduce morbidity and mortality as well as improve functionality and quality of life. Especially in patients with poor oral medication adherence, the use of the two-injection start regimen of long-acting aripiprazole while considering potential drug–drug interactions and extrapyramidal symptoms may improve treatment compliance and reduce the exacerbation risk of psychotic symptoms caused by medication discontinuation.