Primary HIV-1 infection is a relevant period for its virological and epidemiological consequences. Most patients present a symptomatic disease that can be potentially serious, but neurological involvement during primary HIV-1 infection has been poorly studied. The aim of this study was to describe the characteristics and outcomes of primary HIV-1 infection patients presenting neurological symptoms and to compare them with primary HIV-1 infection patients without neurological involvement. Retrospective case-control study (1:3) comparing primary HIV-1 infection patients with and without neurological involvement enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016. Matching criteria included age (±10 years), gender, year of diagnosis (±4 years), and Fiebig stage. The conditional logit model was used for comparisons. Fourteen out of 463 patients (3.02%) enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016 presented neurological symptoms. 28.5% of cases presented as meningitis and 71.5% as meningoencephalitis. Cerebrospinal fluid showed non-specific findings, including pleocytosis with lymphocyte predominance and increased protein levels. All cases required hospitalisation, whereas only 19% of the controls did. No other pathogen was identified in any case, but five patients initiated empirically antimicrobial treatment for other aetiologies until diagnosis was confirmed. CD4/CD8 ratio was significantly lower (p = 0.039) and plasmatic viral load significantly higher in the case group, compared to controls (p = 0.028). Risk factors, HIV-1 tropism, subtype distribution, and prescribed ART regimens were comparable between cases and controls. After 6 months on ART, 92% of cases had undetectable viral load, similar to controls, and CD4/CD8 ratio became also comparable between groups. All cases recovered rapidly with ART and were discharged without sequels. Neurological involvement during primary HIV-1 infection is unusual but serious, always requiring hospitalisation. Diagnosis is difficult because of the wide range of symptoms and similarities with other viral aetiologies. Neurological manifestations during primary HIV-1 infection are associated with a lower CD4/CD8 ratio and with a higher viral load than controls. Immediate ART initiation and rapid viral load decrease are required, allowing complete clinical recovery.