Background and Aims: Long-term primary antibiotic prophylaxis of spontaneous bacterial peritonitis has been suggested to be useful in cirrhotic patients with low ascitic fluid protein levels. However, it is unlikely that all such patients need prophylactic treatment. The aim of this study was to identify the group of cirrhotic patients with low ascitic fluid protein levels at high risk of developing a first episode of spontaneous bacterial peritonitis during outpatient follow-up. Methods: One hundred nine cirrhotic patients with low ascitic fluid protein levels and without previous episodes of spontaneous bacterial peritonitis were followed up in an outpatient clinic. Results: Twenty-eight patients developed a first spontaneous bacterial peritonitis episode. In the multivariate analysis, serum bilirubin level (> 3.2 mg/dL) and platelet count (< 98.000/mm3) independently correlated with the risk of developing the first spontaneous bacterial peritonitis (P < 0.01 and P < 0.05, respectively). According to the median relative risk coefficient, a low-risk group (relative risk < 1.09) and a high-risk group (relative risk > 1.09) were established. The probability of developing a first spontaneous bacterial peritonitis episode at 1-year follow-up was significantly higher in the high risk-group (low-risk group, 23.6%; high-risk group, 55%; P < 0.01) as a consequence of a higher probability of the first community-acquired episode (13.7% vs. 47.6%, respectively, P < 0.01). One-year probability of survival was significantly lower in the high-risk group (low-risk group, 57.6%; high-risk group, 38%, P < 0.05). Conclusions: Cirrhotic patients with low ascitic fluid protein levels (≤ 1 g/dL) and high bilirubin level and/or low platelet count are at high risk of developing a first episode of spontaneous bacterial peritonitis during long-term follow-up.