Research regarding difficult mask ventilation (DMV) combined with difficult laryngoscopy (DL) is extremely limited even though each technique serves as a rescue for one another. Four tertiary care centers participating in the Multicenter Perioperative Outcomes Group used a consistent structured patient history and airway examination and airway outcome definition. DMV was defined as grade 3 or 4 mask ventilation, and DL was defined as grade 3 or 4 laryngoscopic view or four or more intubation attempts. The primary outcome was DMV combined with DL. Patients with the primary outcome were compared to those without the primary outcome to identify predictors of DMV combined with DL using a non-parsimonious logistic regression. Of 492,239 cases performed at four institutions among adult patients, 176,679 included a documented face mask ventilation and laryngoscopy attempt. Six hundred ninety-eight patients experienced the primary outcome, an overall incidence of 0.40%. One patient required an emergent cricothyrotomy, 177 were intubated using direct laryngoscopy, 284 using direct laryngoscopy with bougie introducer, 163 using videolaryngoscopy, and 73 using other techniques. Independent predictors of the primary outcome included age 46 yr or more, body mass index 30 or more, male sex, Mallampati III or IV, neck mass or radiation, limited thyromental distance, sleep apnea, presence of teeth, beard, thick neck, limited cervical spine mobility, and limited jaw protrusion (c-statistic 0.84 [95% CI, 0.82-0.87]). DMV combined with DL is an infrequent but not rare phenomenon. Most patients can be managed with the use of direct or videolaryngoscopy. An easy to use unweighted risk scale has robust discriminating capacity.