Background There are scanty international and even no Egyptian studies addressing the prevalence of obstructive sleep apnea syndrome (OSAS) in railway drivers with an expected high risk of accidents. Thus, it is worth studying and assessing the prevalence and predictors of OSAS among Egyptian railway drivers.Patients and methods This prospective cross-sectional screening study was conducted on 160 Egyptian railway drivers. They were subjected to medical history taking and examination, anthropometric measurements, oxygen saturation (SpO2) by oximetry, arterial blood gases, Friedman obstructive sleep apnea–hypopnea syndrome score measurement, and Arabic version of both Berlin and STOP BANG questionnaires. Then, limited night polysomnography (PSG) was performed in high-risk patients. Finally, full channel PSG was done for positive limited night PSG.Results The prevalence of sleep apnea among the studied cases was 4.22%. There was high statistically significant difference between the non-OSAS group and the OSAS group regarding age less than or equal to 49 years [odds ratio (OR)=11.364], witnessed apneas during sleep (OR=175), weight in kg more than 95 (OR=13.00), PaO2 less than or equal to 88 (OR=31.0), PaCO2 more than 39 (OR=31.0), and average SPO2 less than or equal to 88 (OR=34.0). Regarding parameters of limited night PSG, the apnea–hypopnea index cutoff point was more than or equal to 5 with an area under the curve (AUC) of 100%, O2 desaturation index cutoff point was more than 17.2 with an AUC of 100%; lastly, the average SPO2 cutoff point was less than or equal to 88% with an AUC of 76.4%.Conclusion This study highlights for the first time that the prevalence of OSAS was 4.2% in a sample of Egyptian railway drivers. Our results further point out that weight, neck circumference, systolic blood pressure, PaO2, and PaCO2 are the most useful predictors of suspecting OSAS. Also, parameters of limited PSG are considered a useful tool in confirming suspected patients with OSAS.