Data were collected to characterize whole-house mechanical ventilation (WHMV) and indoor air quality (IAQ) in 55 homes in the Marine climate of Oregon and Cold-Dry climate of Colorado in the U.S. Sixteen homes were monitored for two weeks, with and without WHMV operating. Ventilation airflows; airtightness; time-resolved CO2, PM2.5 and radon; and time-integrated NO2, NOX and formaldehyde were measured. Participants provided information about IAQ-impacting activities, perceptions and ventilation use. All homes had operational cooktop ventilation and bathroom exhaust. Thirty homes had equipment that could meet the ASHRAE 62.2-2010 standard with continuous or controlled runtime and 34 had some WHMV operating as found. Thirty-five of 46 participants with WHMV reported they did not know how to operate it, and only half of the systems were properly labeled. Two-week homes had lower formaldehyde, radon, CO2, and NO (NOX-NO2) when operated with WHMV; and also had faster PM2.5 decays following indoor emission events. Overall IAQ satisfaction was similar in Oregon and Colorado, but more Colorado participants (19 vs. 3%) felt their IAQ could be improved and more reported dryness as a problem (58 vs. 14%). The collected data indicate that there are benefits of operating WHMV, even when continuous use may not be needed because outdoor pollutant concentrations are low and indoor sources do not present substantial challenges.