Objective To describe sedative co-medication patterns across frailty states (robust, prefrail, frail) in people living with HIV using network-based analysis, aiming to identify key medication interactions and network drivers that can guide safer therapeutic approaches. Methods This cross-sectional study analyzed 321 participants using sedatives from the Positive Brain Health Now Cohort (mean age: 53 years), categorized as robust (30.2%), prefrail (47.0%), or frail (22.7%). Sedative use was classified using the Sedative Load Model, and frailty was assessed with a modified Fried Frailty Phenotype. Co-medication networks were constructed for robust, prefrail, and frail groups, with metrics such as Neighborhood Shift Scores (NESH) and Delta Betweenness used to evaluate network dynamics. Edge-level Observed-to-Expected (O/E) ratios highlighted significant co-prescription patterns and associated drug-drug interactions. Results Frail individuals exhibited the most interconnected network, characterized by higher graph density and average degree compared to robust and prefrail groups. Key ”driver” medications identified were mirtazapine (robust-to-prefrail), gabapentin (robust-to-frail), and pregabalin (prefrail-to-frail). In frail individuals, medication pairs with high O/E ratios (e.g., hydromorphone-clonazepam, O/E: 3.07), posed a potential risk for severe drug interactions requiring therapy modification. Robust individuals displayed fewer and less severe drug interactions, whereas prefrail individuals exhibited an intermediate level of complexity. Conclusion Sedative co-medication patterns vary significantly across frailty states in people with HIV, with frailty amplifying risks of severe drug interactions. Identifying key medications as network drivers provides actionable insights to optimize therapeutic approaches, particularly for depression and neuropathic pain management in prefrail and frail stages.