A middle-aged Caucasian man presented with a six-month history of bilateral enlargement of the breasts associated with pain. His hormonal profile was normal and no other underlying cause was identified, we diagnosed him with idiopathic gynecomastia. He is living with HIV, clinically stable (viral load <20copies/mL) and on injectable antiretrovirals cabotegravir/rilpivirine. Tamoxifen is an anti-estrogen recommended for gynecomastia and has been described in persons living with HIV. In this case, tamoxifen could potentially induce the activity of cytochrome P450 3A4 (CYP3A4), reducing rilpivirine concentrations, which consequently may cause virological failure. According to the National Health Service (NHS) guidelines in the UK, an aromatase inhibitor can be used in place of tamoxifen. To date, there have been no reported cases of using anastrozole as a treatment for gynecomastia in people living with HIV, or of its co-administration with antiretrovirals.