This study examined whether different combinations of ambient temperature and relative humidity for the effective wet bulb globe temperature, in conjunction with two different levels of clothing adjustment factors, elicit a similar level of heat strain consistent with the current threshold limit value guidelines. Twelve healthy, physically active men performed four 15-min sessions of cycling at a fixed rate of metabolic heat production of 350 watts. Each trial was separated by a 15-min recovery period under four conditions: (1) Cotton coveralls + dry condition (WD: 45.5 °C dry-bulb, 15% relative humidity); (2) Cotton coveralls + humid condition (WH: 31 °C dry-bulb, 84% relative humidity); (3) Protective clothing + dry condition (PD: 30 °C dry-bulb, 15% relative humidity); and (4) Protective clothing + humid condition (PH: 20 °C dry-bulb, 80% relative humidity). Gloves (mining or chemical) and headgear (helmet or powered air-purifying respirator) were removed during recovery with hydration ad libitum. Rectal temperature (Tre), skin temperature (Tsk), physiological heat strain (PSI), perceptual heat strain (PeSI), and body heat content were calculated. At the end of the 2-hr trials, Tre remained below 38 °C and the magnitude of Tre elevation was not greater than 1 °C in all conditions (WD: 0.9, WH: 0.8, WH: 0.7, and PD: 0.6 °C). However, Tsk was significantly increased by approximately 2.1 ± 0.8 °C across all conditions (all p ≤ 0.001). The increase in Tsk was the highest in WD followed by PD, WH, and PH conditions (all p ≤ 0.001). Although PSI and PeSI did not indicate severe heat strain during the 2-hr intermittent work period, PSI and PeSI were significantly increased over time (p ≤ 0.001). This study showed that core temperature and heat strain indices (PSI and PeSI) increased similarly across the four conditions. However, given that core temperature increased continuously during the work session, it is likely that the American Conference of Governmental Industrial Hygienist's TLV® upper limit core temperature of 38.0 °C may be surpassed during extended work periods under all conditions.