Abstract Background There is a dearth of literature on the impact of TB/HIV co-infection on quality of life (QoL). We conducted a study to assess the change in QoL over a 6-months period and its predictors among HIV-infected patients with and without TB in Ethiopia. Methods 465 HIV-infected patients without TB and 124 TB/HIV co-infected patients were enrolled in a prospective study in February, 2009. 455 (98%) HIV-infected and 97 (78%) TB/HIV co-infected patients were followed for 6 months. Data on QoL at baseline and 6 th month were collected by trained nurses through face to face interviews using the short Amharic version of the World Health Organization Quality of Life Instrument for HIV clients (WHOQOL HIV-Brief). Common Mental Disorder (CMD) was assessed using a validated version of the Kessler-10 scale. Multivariate analysis was conducted using generalized estimating equations (GEE) using STATA to assess change in QoL and its predictors. Results There was a statistically significant improvement of the physical, psychological, social, environmental and spiritual QoL at the 6 th months follow up compared to the baseline for both groups of patients (P