Excluding the presence of obstructive sleep apnea in commercial drivers is valuable, as the syndrome may increase their risk of sleepiness-related accidents. Using polysomnography as the criterion standard, we prospectively compared accuracies of five strategies in excluding the presence of severe sleep apnea and, secondarily, any sleep apnea among 406 commercial drivers. These strategies were as follows: (1) symptoms; (2) body mass index; (3) symptoms plus body mass index; (4) a two-stage approach with symptoms plus body mass index for everyone, followed by oximetry for a subset; and (5) oximetry for all. For excluding severe apnea, the two-stage strategy was highly successful, with 91% sensitivity and specificity, and a negative likelihood ratio of 0.10. This strategy was comparable in accuracy to oximetry, which had a negative likelihood ratio of 0.12, and was 88% sensitive and 95% specific. If we avoided oximetry altogether, then symptoms together with body mass index were 81% sensitive and 73% specific, with a negative likelihood ratio of 0.26. On the other hand, excluding any apnea could not be done with reasonable accuracy unless oximetry was used. We conclude that two-stage screening is likely to be a viable means of excluding severe sleep apnea among commercial drivers.