The Karolinska Sleepiness Scale and Samn-Perelli fatigue ratings, and psychomotor vigilance task performance are proposed as measures for monitoring commercial pilot fatigue. In laboratory studies, they are sensitive to sleep/wake history and circadian phase. The present analyses examined whether they reliably reflect sleep/wake history and circadian phase during transmeridian flight operations. Data were combined from four studies (237 pilots, 730 out-and-back flights between 13 city pairs, 1-3-day layovers). Sleep was monitored (wrist actigraphy, logbooks) before, during and after trips. On duty days, sleepiness, fatigue and mean response speed were measured pre-flight and at the top of the descent. Mixed-model analysis of variance examined associations between these measures and sleep/wake history, after controlling for operational factors. Circadian phase was approximated by local (domicile) time in the city where each trip began and ended. More sleep in the 24 h prior to duty was associated with lower pre-flight sleepiness and fatigue and faster response speed. Sleepiness and fatigue were greater before flights departing during the domicile night and early morning. At the top of the descent, pilots felt less sleepy and fatigued after more in-flight sleep and less time awake. Flights arriving in the early-mid-morning (domicile time) had greater sleepiness and fatigue and slower response speeds than flights arriving later. Subjective ratings showed expected associations with sleep/wake history and circadian phase. The response speed showed expected circadian variation but was not associated with sleep/wake history at the top of the descent. This may reflect moderate levels of fatigue at this time and/or atypically fast responses among pilots.