Researchers' aim was to investigate if patients/physicians characteristics could differently affect males/females health care expenditure. In 2009/2010, a health-related-quality-of-life (HRQL) measure was distributed to 887 general practitioners' (GP) patients in Siena's province-Italy. Severity of diseases was calculated through Cumulative Illness Rating Scale Severity Index (CIRS-SI). Information about GPs' gender and age and patients' gender, age, and socio-economic variables were recorded. 2012 data about pharmaceutical, outpatient and hospital expenditure were obtained. Multivariate regression was carried out. In males, hospital expenditure increased with higher CIRS-SI and female GP whilst in females it was not influenced by any of the variables. Outpatient and pharmaceutical expenditure increased with aging, higher CIRS-SI, and lower HRQL and education, both in males and females. Gender differences in health expenditure determinants emerged for hospital expenditure.