The aim of this review is to understand if Spirulina can significantly improve the CD4+ cell count in patients with HIV. PubMed was searched up to November 2021 for relevant trials, and seven studies were found to match our inclusion criteria. Overall, available evidence indicates that Spirulina might be useful to improve the CD4+ T-lymphocyte count in patients with HIV. A more pronounced effect is likely to be observed for a 10-gram daily dose of Spirulina, when this supplement is administered for 6 months, while smaller amounts given for shorter periods of time seem to be less effective. High-quality Spirulina-derived products are necessary to ensure the best clinical safety and avoid contaminants. Further studies on the topic are needed.