Long-Term Clinical Performance of Dental Gels and Resin Infiltration for White Spot Lesions: A Systematic Review

White spot lesions (WSLs) are non-cavitated enamel lesions for which treatment success depends not only on initial lesion arrest or aesthetic improvement but also on long-term stability. This systematic review aimed to evaluate the long-term clinical, aesthetic, and remineralization outcomes of WSL treatments, with particular emphasis on treatment longevity and biomaterial-based approaches. A systematic search was conducted in PubMed, Scopus, and the Cochrane Library. Randomized controlled trials involving permanent teeth with ICDAS-assessed WSLs and a minimum follow-up of 12 months were eligible. Interventions included resin infiltration, fluoride-based therapies, remineralizing gels, casein phosphopeptide–amorphous calcium phosphate (CPP-ACP) formulations, hydroxyapatite, self-assembling peptides, microabrasion, bleaching, and combined approaches. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Due to substantial clinical and methodological heterogeneity, a conventional pooled meta-analysis was not considered appropriate. Nine publications representing eight independent randomized controlled trials, with follow-up periods of 12–36 months, were included. Resin infiltration demonstrated the most consistent long-term aesthetic benefits and sustained reductions in visible WSL area. Non-invasive approaches, including fluoride-based therapies and remineralizing gels, generally improved outcomes from baseline; however, the additional benefits of specific formulations, including CPP-ACP/CPP-ACPF and fluoride-containing gels or varnishes, were inconsistent compared with conventional fluoride toothpaste. Limited quantitative comparisons favored resin infiltration over fluoride varnish, CPP-ACP, and fluoride toothpaste for lesion-area reduction. The certainty of evidence was low for aesthetic outcomes and very low to low for remineralization and lesion progression outcomes. Resin infiltration showed the most consistent long-term clinical and aesthetic benefits, maintained for up to 24 months. Non-invasive strategies may support lesion regression and remineralization, but their additional long-term benefits remain uncertain and appear dependent on formulation and treatment protocol. However, direct evidence of treatment durability was limited, as several trials assessed long-term effectiveness during continuous or repeated treatment rather than the maintenance of an initially achieved response. Recurrence and retreatment were inconsistently reported, and prevention of new WSLs represented a distinct clinical outcome. Further well-designed trials with standardized outcomes and longer follow-up are needed to establish the comparative effectiveness and longevity of biomaterial-based treatments for WSLs.