Lyme disease (Borrelia burgdorferi infection) is the most common vector-transmitted disease in the United States. The majority of human Lyme disease (LD) cases occur in the summer months, but the timing of the peak occurrence varies geographically and from year to year. We calculated the beginning, peak, end, and duration of the main LD season in 12 highly endemic states from 1992 to 2007 and then examined the association between the timing of these seasonal variables and several meteorological variables. An earlier beginning to the LD season was positively associated with higher cumulative growing degree days through Week 20, lower cumulative precipitation, a lower saturation deficit, and proximity to the Atlantic coast. The timing of the peak and duration of the LD season were also associated with cumulative growing degree days, saturation deficit, and cumulative precipitation, but no meteorological predictors adequately explained the timing of the end of the LD season.