The Cleveland Indians had the highest run differential by a team in a game in 2006, with a differential of 18 runs versus the Yankees on July 4, 2006.

Interpreted as:

biggest win margin in one regular-season game in 2006

	TEAM	DIFF	DATE	TM		OPP	RESULT	AB	R	H	2B	3B	HR	RBI	BB	HBP	SO	SB	CS	PA	TB	XBH	SH	SF	IBB	GIDP	AVG	OBP	SLG	OPS
1	Indians	18	7/4/2006	CLE	vs	NYY	W 19-1	44	19	21	6	0	6	19	6	1	6	0	0	52	45	12	1	0	0	0	.477	.549	1.023	1.572
2	Tigers	17	4/29/2006	DET	vs	MIN	W 18-1	48	18	23	6	0	4	15	2	1	10	1	0	51	41	10	0	0	0	0	.479	.510	.854	1.364
3	Yankees	15	9/25/2006	NYY	@	TBD	W 16-1	45	16	20	3	0	4	16	5	1	3	0	0	51	35	7	0	0	0	2	.444	.510	.778	1.288
4	Tigers	15	9/15/2006	DET	vs	BAL	W 17-2	44	17	19	6	1	4	16	5	0	7	1	0	49	39	11	0	0	1	0	.432	.490	.886	1.376
5	Orioles	15	8/19/2006	BAL	vs	TOR	W 15-0	36	15	12	5	0	3	14	4	1	8	0	0	41	26	8	0	0	1	1	.333	.415	.722	1.137
6	Reds	14	8/22/2006	CIN	vs	HOU	W 14-0	37	14	15	2	0	4	14	5	0	6	0	0	42	29	6	0	0	1	1	.405	.476	.784	1.260
7	Rangers	14	8/9/2006	TEX	@	OAK	W 14-0	44	14	17	5	0	5	13	6	0	7	0	1	51	37	10	0	1	1	0	.386	.451	.841	1.292
8	Rangers	14	7/13/2006	TEX	@	BAL	W 15-1	42	15	19	2	0	6	15	6	1	3	1	0	50	39	8	0	1	0	2	.452	.520	.929	1.449
9	Mets	14	7/8/2006	NYM	vs	FLA	W 17-3	40	17	16	2	2	3	17	4	1	4	0	0	45	31	7	0	0	0	0	.400	.467	.775	1.242
10	White Sox	14	6/20/2006	CWS	vs	STL	W 20-6	49	20	24	3	0	4	19	1	2	5	0	0	52	39	7	0	0	0	0	.490	.519	.796	1.315
11	Brewers	14	4/29/2006	MIL	@	CHC	W 16-2	43	16	16	3	0	6	15	11	0	5	0	0	54	37	9	0	0	0	0	.372	.500	.860	1.360
12	Indians	14	4/18/2006	CLE	@	BAL	W 15-1	47	15	20	2	0	2	14	3	1	5	1	1	51	28	4	0	0	0	0	.426	.471	.596	1.066
13	Mets	13	9/30/2006	NYM	@	WSH	W 13-0	39	13	12	2	0	5	13	7	0	8	1	0	47	29	7	1	0	1	0	.308	.413	.744	1.157
14	Indians	13	9/25/2006	CLE	vs	CWS	W 14-1	36	14	13	3	0	1	12	5	0	8	0	1	42	19	4	0	1	1	0	.361	.429	.528	.956
15	Phillies	13	8/14/2006	PHI	vs	NYM	W 13-0	35	13	12	3	0	3	12	3	2	10	1	0	40	24	6	0	0	0	1	.343	.425	.686	1.111
16	Indians	13	8/13/2006	CLE	vs	KCR	W 13-0	36	13	11	3	0	3	13	4	0	7	0	0	40	23	6	0	0	0	0	.306	.375	.639	1.014
17	Astros	13	8/9/2006	HOU	vs	PIT	W 14-1	38	14	15	2	0	6	14	6	0	4	0	1	44	35	8	0	0	0	1	.395	.477	.921	1.398
18	Twins	13	7/31/2006	MIN	vs	TEX	W 15-2	41	15	18	1	1	2	15	2	0	2	0	0	44	27	4	0	1	0	1	.439	.455	.659	1.113
19	Marlins	13	7/31/2006	FLA	@	PHI	W 15-2	44	15	17	6	1	4	15	4	1	7	0	1	49	37	11	0	0	1	0	.386	.449	.841	1.290
20	Rangers	13	7/30/2006	TEX	vs	KCR	W 15-2	41	15	19	6	0	2	14	5	0	2	1	0	48	31	8	1	1	2	1	.463	.511	.756	1.267
21	Devil Rays	13	7/29/2006	TBD	@	NYY	W 19-6	43	19	17	6	0	4	18	5	2	5	1	0	52	35	10	1	1	0	0	.395	.471	.814	1.285
22	White Sox	13	7/4/2006	CWS	vs	BAL	W 13-0	42	13	18	6	0	2	13	5	1	8	2	0	48	30	8	0	0	1	1	.429	.500	.714	1.214
23	Mets	13	6/11/2006	NYM	@	ARI	W 15-2	42	15	15	7	1	0	15	10	1	13	3	0	54	24	8	1	0	0	0	.357	.491	.571	1.062
24	Marlins	13	6/3/2006	FLA	@	COL	W 13-0	43	13	18	3	0	3	13	2	0	6	2	0	46	30	6	1	0	0	2	.419	.444	.698	1.142
25	Diamondbacks	13	5/20/2006	ARI	vs	ATL	W 13-0	35	13	15	6	0	2	13	6	2	3	0	0	45	27	8	1	1	3	3	.429	.523	.771	1.294