Objectives. We examined health-related quality of life in adults who became physically active at recommended levels over a 10-year period compared with adults with different physical activity patterns. Methods. We examined men and women aged 26 to 70 years (mean [SD] = 47.4 [10.1]) in the Doetinchem Cohort Study 3 times between 1995 and 2009. We distinguished participants who became physically active (n = 618), remained active (n = 1286), remained inactive (n = 727), became physically inactive (n = 535), or with varying activity levels (n = 455) over 10 years. We used multivariable linear regression analyses to determine differences in health-related quality of life (survey similar to the 36-Item Short-Form Health Survey) at 10-year follow-up. Results. Adults who became physically active reported better physical functioning, vitality, and general health after 10 years than did persistently inactive adults and adults who became inactive. They also reported less bodily pain and better social functioning than adults who became inactive. No differences were observed with adults who remained active or with varying activity levels. Conclusions. Adopting a physically active lifestyle may result in a better health-related quality of life, comparable to remaining physically active over 10 years.