The annual suicide rate rose by 0.7 percent between 1999 and 2005, but among white Americans between the ages of 40 to 64 it rose 2.7 percent, according to the study.
For middle-aged white women the suicide rate rose 3.9 percent, the study reported.
By contrast, the suicide rate among African-Americans decreased during the same period, and remained unchanged among Asian Americans and Native Americans, said the study, published in the online edition of the American Journal of Preventive Medicine.
"The results underscore a change in the epidemiology of suicide, with middle-aged whites emerging as a new high-risk group," said co-author of the study Susan Baker, a professor with the Johns Hopkins Bloomberg School's Center for Injury Research and Policy.
"Historically, suicide prevention programs have focused on groups considered to be at highest risk - teens and young adults of both genders as well as elderly white men," she said.
The research, said Baker, "tells us we need to refocus our resources to develop prevention programs for men and women in their middle years."
Researchers found that firearms remain the predominant method for suicides, but that the rate of firearm suicides decreased during the study period.
Suicide by hanging or suffocation soared among men, the study found, with a 6.3 percent annual increase.
Hanging or suffocation accounted for 22 percent of all suicides by 2005, coming in second place behind firearms. Poisoning took third with 18 percent.
Reasons behind the spike in the suicide rate remain unclear, the study said.
"While it would be straightforward to attribute the results to a rise in so-called mid-life crises, recent studies find that middle age is mostly a time of relative security and emotional well being," said Baker.
"Further research is warranted to explore societal changes that may be disproportionately affecting the middle-aged in this country," she said.