This is a study of the impact of specific and overall comorbidity on health-related quality of life (HRQoL) in men with primary total knee arthroplasty (TKA). In a population-based sample of male veterans who responded to a cross-sectional survey using the validated short-form 36 for veterans (SF-36 V) and had undergone primary TKA prior to survey, eight SF-36 V domain and two summary scores (physical and mental component (PCS and MCS) summary) were compared using multivariable-adjusted multiple linear regressions between patients with and without five comorbidities--chronic obstructive pulmonary disease (COPD)/asthma, diabetes, depression, hypertension, and heart disease. Analyses were adjusted for age, five comorbidities, and time since TKA. Two hundred ninety-three male patients constituted the analytic set with mean (SD) age of 70.3 (8.8) years; 97% were Caucasian and mean (SD) duration since TKA was 2.1 (0.7) years. COPD/asthma was associated with significantly lower adjusted MCS (mean +/- standard error of mean, 47.1 +/- 0.7 vs. 43.1 +/- 1.2; p <or= 0.001) and PCS (30.1 +/- 0.6 vs. 27.7 +/- 1.0; p < 0.05), depression with significantly lower MCS (48.9 +/- 0.7 vs. 37.6 +/- 1.2; p <or= 0.001) but not PCS, hypertension with significantly lower MCS (47.0 +/- 0.7 vs. 44.3 +/- 1.0; p < 0.05) but not PCS, and heart disease with significantly lower MCS (47.4 +/- 0.8 vs. 44.2 +/- 0.9; p <or= 0.001) and PCS (30.5 +/- 0.7 vs. 28.1 +/- 0.8; p < 0.05). Diabetes was not associated with lower MCS or PCS. The overall number of comorbidities was associated with lower MCS and PCS (p <or= 0.001 for both). Medical and psychiatric comorbidity impacts physical and mental/emotional HRQoL in patients with primary TKA. The impact differs by comorbidity. Higher comorbidity load negatively impacts both physical and mental/emotional HRQoL.