Enrollment for most Part D beneficiaries is voluntary. The initial enrollment period took place from November 15, 2005 through May 15, 2006. Potential beneficiaries who did not enroll by the May 15 deadline (or within a given time frame after their initial eligibility date) incurred a late-enrollment penalty of 1% per month based on the average cost of the premium until their enrollment.

Annual enrollment periods for Medicare Part D begin on November 15 of the prior plan year. The initial enrollment period for the second year of Medicare Part D started November 15, 2006. In its first year, beneficiaries eligible for both Medicaid and Medicare (dual eligibles) were transferred from Medicaid prescription drug coverage to a Medicare Part D plan on January 1, 2006. Enrollment in January 2008 was 25.4 million, which was 6.2% higher than the 2007 enrollment. (An additional 14.2 million Medicare beneficiaries received drug coverage from other sources such as veterans benefits and retirement plans.

As of 2008 there were 1,824 stand-alone Part D plans available. The number of available plans varied by region. The lowest was 27 (Alaska) and the highest was 63 (Pennsylvania & West Virginia). This allows participants to choose a plan that best meets their individual needs. Plans can choose to cover different drugs, or classes of drugs, at various co-pays, or choose not to cover some drugs at all.