The clinical significance of pleural effusions (PLEs) in the setting of acute pericarditis remains poorly investigated. We sought to identify predictive factors for PLEs and their association with the short- and long-term prognosis of patients with acute pericarditis. We enrolled 177 patients hospitalized with a first episode of acute pericarditis. In all cases an extensive clinical, biochemical, and diagnostic work-up to detect PLEs and establish etiological diagnosis was performed. All patients included were prospectively followed for a maximum of 18 months (median 12, range 1-18) and complications were recorded. PLEs were detected in n = 94 cases (53.1% of the cohort; bilateral 53.2%, left-sided 28.7%, right-sided 18.1%) and were strongly associated with c-reactive protein (CRP) levels at admission (rho = 0.328, p < 0.001). In multivariate logistic regression, independent predictors for PLEs were female gender (OR = 2.46, 95% CI 1.03-5.83), age (per 1-year increment OR = 1.030, 95% CI 1.005-1.056), CRP levels (per 1 mg/L increment OR = 1.012, 95% CI 1.006-1.019) and size of pericardial effusion (per 1 cm increment, OR = 1.899, 95% CI 1.228-2.935). Bilateral PLEs were associated with increased risk for in-hospital cardiac tamponade (OR = 7.52, 95% CI 2.16-26.21). There was no association of PLEs with new onset atrial fibrillation or pericarditis recurrence during long-term follow-up (χ2  = 0.003, p = 0.958). We conclude that PLEs are common in patients hospitalized with a first episode of acute pericarditis. They are related to the intensity of inflammatory reaction, and they should not be considered necessarily as a marker of secondary etiology. Bilateral PLEs are associated with increased risk of in-hospital cardiac tamponade, but do not affect the long-term risk of pericarditis recurrence.