Despite widespread acceptance of total knee replacement surgery's clinical effectiveness, variation persists in long-term functional outcome. Our aim was to quantify the relative contributions of physical and emotional coexisting conditions to the variation in improvement in 12-month post-total knee replacement physical function. Data from 165 patients who had primary total knee replacement (62% women; mean age 68 years) were evaluated. Eighty-four percent had at least one comorbid illness, with cardiovascular conditions the most prevalent (61%). Mean improvement in 12-month general function (Short Form-36 Physical Component Score) and knee-specific function (Western Ontario and McMaster Universities Osteoarthritis Index) was similar for patients with and without comorbid medical diagnoses. Adding coexisting conditions to age, gender, and baseline physical function did not improve the model's ability to explain variation in 12-month physical function as measured by either Short Form-36 Physical Component Score or Western Ontario and McMaster Universities Osteoarthritis Index. Although coexisting medical conditions did not predict the degree of 12 month post-total knee replacement functional improvement, poorer pre-total knee replacement emotional health (Short Form-36 Mental Component Score) was associated with smaller improvements in Short Form-36 Physical Component Score and Western Ontario and McMaster Universities Osteoarthritis Index. The lack of a relationship between the presence of coexisting medical diagnoses and 12-month physical function in this study is important for patients and orthopedic surgeons.