Cooling vests alleviate heat strain. We quantified the perceptual and physiological heat strain and assessed the effects of wearing a 21°C phase change material cooling vest on these measures during work shifts of COVID-19 nurses wearing personal protective equipment (PPE). Seventeen nurses were monitored on two working days, consisting of a control (PPE only) and a cooling vest day (PPE + cooling vest). Sub-PPE air temperature, gastrointestinal temperature (T
gi
), and heart rate (HR) were measured continuously. Thermal comfort (2 [1–4]
versus
1 [1–2], p
condtition
< 0.001) and thermal sensation (5 [4–7]
versus
4 [2–7], p
condition
< 0.001) improved in the cooling vest
versus
control condition. Only 18% of nurses reported thermal discomfort and 36% a (slightly) warm thermal sensation in the cooling vest condition
versus
81% and 94% in the control condition (OR (95%CI) 0.05 (0.01–0.29) and 0.04 (<0.01–0.35), respectively). Accordingly, perceptual strain index was lower in the cooling vest
versus
control condition (5.7 ± 1.5
versus
4.3 ± 1.7, p
condition
< 0.001, respectively). No differences were observed for the physiological heat strain index T
gi
and rating of perceived exertion across conditions. Average HR was slightly lower in the cooling vest
versus
the control condition (85 ± 12
versus
87 ± 11, p
condition
= 0.025). Although the physiological heat strain among nurses using PPE was limited, substantial perceptual heat strain was experienced. A 21°C phase change material cooling vest can successfully alleviate the perceptual heat strain encountered by nurses wearing PPE.