Background <p>There is no consensus on the antibiotic course or type of surgical treatment in streptococcal periprosthetic-joint infections (PJIs). We aimed to compare the treatment failure rate at 2 years of PJIs caused by streptococci to PJIs caused by other pathogens and identify factors associated with failure.</p> Methods <p>It was a single-center retrospective cohort study conducted between 2009 and 2019. We included all patients aged ≥ 18&#xa0;years undergoing treatment for hip or knee PJI with a 2-year follow-up. We analyzed the treatment failure rate at 2&#xa0;years of streptococcal PJIs versus PJIs caused by other pathogens with failure defined as a non-successful treatment using the Delphi-based international multidisciplinary consensus of success. We also analyzed factors associated with failure including streptococcal etiology and type of treatment.</p> Results <p>We included 404 patients; 62 (15%) had a streptococcal PJI, of which 14 (23%) exhibited treatment failure at 2&#xa0;years. The treatment failure rate was similar to that for PJIs caused by other pathogens (21%, 71/342) (<i>P</i> = 0.78). Streptococci were not associated with failure (OR = 1.55, 95% CI 0.62–3.89, <i>P</i> = 0.35). However, <i>Streptococcus dysgalactiae</i> (OR = 9.45, 95% CI 1.37–65.46, <i>P</i> = 0.02) and debridement, antibiotics and implant retention (DAIR) (OR = 9.31, 95% CI 1.80–48.20, <i>P</i> = 0.008) were associated with failure among patients with a streptococcal PJI.</p> Conclusions <p>The treatment failure rate of streptococcal PJIs was similar to that for PJIs caused by other pathogens. However, <i>Streptococcus dysgalactiae</i> and DAIR were factors associated with failure among patients with a streptococcal PJI. Our results suggest that streptococcal PJIs, especially <i>Streptococcus dysgalactiae</i> PJIs, should be surgically treated more aggressively with an implant exchange.</p>