Marek’s disease (MD) strain CVI988 is the most-protective commercially available vaccine against very virulent plus (vv+) Marek’s disease virus (MDV). However, its use in meat-type chickens has been controversial. While several countries have been using CVI988 for more than 40 yr, others do not authorize its use or it is restricted mainly to layers. The use of CVI988 in meat-type chickens will be necessary in the future in areas where other vaccine protocols fail. The objective of this study was to evaluate factors (vaccine dose, vaccine origin, chicken genetics, age and route of vaccination, and combination with other MD vaccines) influencing the efficacy of CVI988 against MD in meat-type chickens. Three animal experiments were conducted in which various vaccine protocols using CVI988 were tested for their protection against challenge with vv+ strain 648A by contact at day of age. Experiments 1 and 2 were to compare the efficacy of CVI988 vaccines from three different origins (CVI988-A, CVI988-B, and CVI988-C) and evaluate the effect of vaccine dose and chicken genetics. Experiment 3 was to evaluate the effect of adding CVI988 vaccine to various vaccine protocols using other MD vaccines of serotypes 2 (SB-1) and 3 (rHVT). Our results show that, regardless of the origin of the vaccine, protection against early challenge with 648A was good when vaccines were administered at a high dose (>3000 plaque-forming units [PFU]). Differences among vaccines, however, were detected even when using a high dose in experiment 2 (vaccine CVI988-B conferred higher protection than did CVI988-C) but not in Experiment 1 (CVI988-B was compared to CVI988-A). The use of a fixed low dose (2000 PFU) of vaccine resulted in reduction in protection, and such reduction was more remarkable when using CVI988-A. No statistically significant differences were found when we compared the efficacy of CVI988 in two different genetic lines of broiler chickens (G1 and G2). Vaccination protocols that included CVI988 had better protection than protocols that only included MD vaccines of serotypes 2 and 3. This was true regardless of the vaccine protocol used (CVI988/rHVT+SB-1; CVI988+rHVT+SB-1/None; rHVT+SB-1/CVI988; wherein the vaccine before the slash (/) was administered in ovo at embryonation day 18 and the vaccine after the slash was administered at day of age, subcutaneously). When only vaccines of serotypes 2 and 3 were used, protection against early challenge with vv+MDV was higher when vaccines were administered in ovo (rHVT+SB-1/None) than if vaccines were administered at hatch (None/rHVT+SB-1). Monitoring vaccine DNA load in feather pulp (FP) samples at 1 wk was used to monitor vaccination, and results showed that differences in vaccine replication exist among vaccines but such differences were not necessarily related to protection (r = 0.41, P > 0.05). Monitoring load of challenge MDV DNA in FP at 21 days was conducted, and results correlated (r = 0.85, P < 0.05) with the percentage of chickens with MD lesions at the termination of the study, confirming that early diagnosis is a very powerful tool with which to evaluate protection.