Particulate matter (PM) has well-known negative health effects on humans. PM exposure occurs mainly indoors because people spend most of their time inside buildings, especially in their homes. This study aimed at investigating the impact of the principal outdoor factors, house characteristics and indoor activities on size-fractionated PM concentrations in a real exposure scenario consisting of 60 living rooms in the province of Lodi (River Po Valley, Northern Italy), characterized by high pollution levels. Nearby road traffic played a pivotal role for all the studied fractions, with heavy duty vehicles affecting the coarser fractions especially when building density was lower. PM2.5–10 arose also from indoor determinants linked to cleaning activities and house occupancy and was inversely related with house volume. Statistical analysis showed that ambient PM10 was a reliable predictor of PM fractions <2.5 μm, but other indoor sources should be considered, such as ETS for PM0.5 and open fireplaces use for the PM0.5-1. Some protective factors were identified, such as the use of exhaust ventilation in kitchens (PM0.5–1) and sealed windows and doors (PM0.25). Some determinants were also season-related (open fireplaces use, floor level, built-on garages). In conclusion, the study provides an insight on the main PM determinants commonly present in residential environments. The results can be useful in addressing some self-corrected choices by home occupants and in developing meaningful risk mitigation strategies by local institutions.