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Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV-1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies.