This case describes successful management of a man with perinatally acquired HIV complicated by incomplete adherence, multidrug-resistant HIV and opportunistic infections—cryptococcal meningitis and mycobacterium avium intracellulare. Initial treatment included antifungal and antimycobacterials with oral antiretroviral therapy (ART), but persistent high HIV viral load (>100 000 copies/mL) prompted initiation of long-acting injectable ART (LAI-ART) with cabotegravir and rilpivirine combined with adjunct oral nucleoside reverse transcriptase inhibitor therapy (emtricitabine/tenofovir). This combination is expected to have reduced antiviral activity secondary to resistant mutations; notably, high-level resistance to emtricitabine and intermediate resistance to rilpivirine. To attenuate further resistance, 4-weekly dosing of LAI-ART was used. This regimen led to viral suppression within 4 weeks, which remains suppressed (>1 year) and successful immune reconstitution (CD4 cell count of 209 cells/µL/18.7%), despite challenges with adherence to oral medications. This case highlights the feasibility and effectiveness of LAI-ART in managing complex resistance and adherence in perinatally acquired HIV.