Background: Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. Objective: To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. Methods: This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. Results: No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. Conclusions: In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated.