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HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND.Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network.We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection.We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03–7.9) and 2.6 (95% CI 1.03–6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6–70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1–21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age.Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.