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Objective: The aim of this study was to evaluate and compare the clinical behavior of indirect onlays/overlays made of lithium disilicate and composite resin and to investigate risk factors associated with restoration failures. Methods: 112 indirect partial coverage posterior restorations (onlays and overlays) placed in 51 adult patients between January 2014 and December 2020 were examined. The restorations were evaluated using selected FDI criteria (color match, surface gloss, anatomic form, fracture of restorative material, tooth cracks and fractures, marginal discoloration, marginal integrity and recurrence of initial pathology). The survival of the restorations was analyzed using Kaplan–Meier method. Risk factors (type of restoration, type of tooth, tooth vitality, smoking) were investigated using Cox regression analysis. Risk estimation was conducted for each evaluated criterion (p < 0.05). Results: For composite restorations, the estimated survival rate was 94.2% after 5 years, dropping to 74.3% in 7.9 years and continued falling to less than 60% after 8.2 years. On the contrary, for lithium disilicate restorations the estimated survival rate was 90.9% after 5 years, dropped to 85.2% after 5.5 years remaining stable thereafter. Lithium disilicate onlays demonstrated significantly better performance than lithium disilicate overlays. Cox regression analysis did not reveal any significant association between the survival of the indirect partial restorations and restoration material, tooth type, restoration type and history of endodontic treatment. However, smoking was found to be a statistically significant risk factor (p < 0.05). Conclusions: Lithium disilicate and composite indirect restorations exhibited comparable survival rates at the early observation period. However, lithium disilicate partial coverage restorations demonstrated more favorable clinical behavior compared to composite in the long term, with statistical significance observed in ceramic vs. composite onlays.