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Lack of adherence is a key barrier to a successful human immunodeficiency virus (HIV) treatment and prevention. We report on an ultra-long-acting (ULA) biodegradable polymeric solid implant (PSI) that can accommodate one or more antiretrovirals (eg, dolutegravir (DTG) and rilpivirine (RPV)) at translatable human doses (65% wt.) in a single implant. PSIs are fabricated using a three-step process:(a) phase inversion of a drug/polymer solution to form an initial in-situ forming solid implant,(b) micronization of dried drug-loaded solid implants, and (c) compression of the micronized drug-loaded solid powder to generate the PSI. DTG and RPV can be pre-combined in a single PLGA-based solution to make dual-drug PSI; or formulated individually in PLGA-based solutions to generate separate micronized powders and form a bilayer dual-drug PSI. Results showed that in a single or bilayer dual-drug PSI, DTG and RPV …