To date, a cumulative meta-analysis of the effects of supplementation with a combination of prilled C16:0 and C18:0 fatty acids (PFA) that includes all study designs has not been completed. The objective of the current analysis was to examine dry matter intake (DMI), milk yield (MY), and milk component production responses when lactating cows were supplemented with PFA. Data were extracted from 25 peer-reviewed publications and the final data set included 73 treatments, with 39 treatments supplementing PFA and 34 non-supplemented control treatments (CON). Dietary nutrient concentrations (DM%; range) were 17.1% CP [12.0 – 20.1%], 26.1% starch [17.3 – 37.4%], and 33.7% NDF [27.2 – 48%]. A random-effects model with the random effect of study was chosen to estimate the mean of the sampling distribution of possible effect sizes, and studies were weighted by the inverse of their variance. Weighted mean differences between PFA and CON treatments as well as standard errors of the differences between means are reported. The average amount of C16:0 and C18:0 supplementation across studies was 632 ± 222.4 g/d. DMI was not affected by PFA supplementation (22.01 vs 22.07 ± 0.18 kg/d; P = 0.75), while net energy intake increased with PFA supplementation (37.59 vs 35.46 ± 0.62 Mcal/d; P < 0.01). PFA increased MY (33.78 vs 32.55 ± 0.26 kg/d; P < 0.01) and milk fat percentage (3.53 vs 3.45 ± 0.03%; P < 0.01). There was no change in milk protein concentration (3.12 vs 3.14 ± 0.02%; P = 0.34) and a tendency for decreased milk lactose concentration (4.85 vs 4.89 ± 0.02%; P = 0.06) with PFA. Yields of milk fat and milk protein were increased (1.17 vs 1.11 ± 0.01 kg/d and 1.04 vs. 1.01 ± 0.01 kg/d, respectively; P < 0.01) with PFA supplementation, while milk lactose yield was unaffected (1.83 vs 1.78 ± 0.03 kg/d; P = 0.16). Supplementation with a combination of C16:0 and C18:0 fatty acids resulted in a significant increase in MY, milk fat and milk protein yield and net energy intake, while causing no appreciable decrease in DMI.