Hexamethylene diisocyanate (HDI)-based polyisocyanates are widely used in formulating polyurethane coatings. These polyisocyanates contain a small amount of HDI monomer and the American Conference of Governmental Industrial Hygienists (ACGIH) recommends an eight-hour time-weighted average (TWA) threshold limit value (TLV) of 5 ppb for HDI. Some polyurethane (PU) paint applicators have used air-purifying paint spray respirators with organic vapor cartridges and particulate pre-filters. In this study, the effect of typical paint solvents on the efficiency of organic vapor cartridges (OVC) for HDI vapor was tested. A Teflon-coated polycarbonate exposure chamber was constructed. Three OVCs were simultaneously tested in an atmosphere containing HDI vapor and solvents. The test atmosphere was generated by evaporating a mixture of paint solvents containing n-butyl acetate, propylene glycol mono methyl ether acetate, toluene and methyl ethyl ketone, and neat HDI. The target challenge concentrations were 20 times the TLV for HDI and 10 times the combined TLV for the solvent mixture. The test atmosphere, with 20 or 80 percent relative humidity and at room temperature, was drawn through each cartridge at 32 L/min for 40 hours. However, in the last 8 hours of the test, the atmosphere had only HDI vapor. The pre- and the post-cartridge atmospheres were periodically sampled for HDI and the solvents. The study concluded that under the test conditions there was no detectable breakthrough of HDI from the OVCs. The average calculated efficiency of the OVCs, based on the HDI analytical limit of quantitation, was >99.4 percent for the 40 hours tested. The overall average challenge concentration of HDI was 105 ppb and the average combined solvent concentration was 3,176 mg/m3. The cartridges were saturated with solvents within the first 10 hours of testing; nevertheless, continued challenging with HDI vapor and solvents did not show any HDI breakthrough. Solvent breakthrough and breathing resistance, rather than HDI breakthrough, would be the key parameters in life expectancy calculations for cartridge change out schedules.